Piperazine substituted aryl benzodiazepines and their use as dopamine receptor antagonists for the treatment of psychotic disorders

ABSTRACT

Described herein are antipyschotic compounds of formula (I) 
                         
wherein,
         A is an optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, O, and S;   Alk is (C 1-4 ) alkylene optionally substituted with OH, methoxy, ethoxy, or F;   Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic;   R 1  is hydrogen or (C 1-4 ) alkyl optionally substituted with OH, OR 3 , or OCH 2 CH 2 OH,
           wherein R 3  is (C 1-2 ) alkyl;   
           R 2  is H, (C 1-6 ) alkyl, halogen, fluorinated (C 1-6 ) alkyl, OR 4 , SR 4 , NO 2 , CN, COR 4 , CONR 5 R 6 , SO 2 NR 5 R 6 , NR 5 R 6 , NR 5 COR 4 , NR 5 SO 2 R 4 , or optionally substituted phenyl,
           wherein   R 4  is hydrogen, (C 1-6 ) alkyl, fluorinated (C 1-6 ) alkyl, or optionally substituted phenyl,   R 5  and R 6  are independently hydrogen, (C 1-6 ) alkyl, or optionally substituted phenyl;   
           Z is one or two substituents independently selected from hydrogen, halogen, (C 1-6 ) alkyl, fluorinated (C 1-6 ) alkyl, OR 7 , SR 7 , NO 2 , CN, COR 7 , CONR 8 R 9 , SO 2 NR 8 R 9 , NR 8 SO 2 R 7 , NR 8 R 9 , or optionally substituted phenyl,
           wherein   R 7  is hydrogen, (C 1-6 ) alkyl, fluorinated alkyl, or optionally substituted phenyl,   R 8  and R 9  are independently hydrogen, (C 1-6 ) alkyl, or optionally substituted phenyl;   
           and salts, solvates, and crystal forms thereof.
 
Also described are the use of the compounds of formula (I) as antagonists of the dopamine D 2  receptor and as agents for the treatment of psychosis and bipolar disorder, and pharmaceutical formulations of the compounds of formula (I).

This is the national phase application, under 35 USC 371, for PCT/US03/06708, filed 17 Mar. 2003, which, claims the benefit, under 35 USC 119(e), of US provisional application 60/368,670, filed 28 Mar. 2002.

BACKGROUND OF THE INVENTION

Currently there are many drugs available for the treatment of disorders of the central nervous system. Among these drugs is a category known as antipsychotics for treating serious mental conditions such as schizophrenia and schizophreniform illnesses. The drugs available for such conditions are often associated with undesirable adverse events, and there is a need for better products that control or eliminate the symptoms in a safer and more effective way.

Patients suffering from schizophrenia, a condition of unknown etiology, exhibit a group of both positive and negative symptoms. Positive symptoms include delusions, hallucinations, disordered thoughts, and disorganized speech, while negative symptoms include flat affect, anhedonia, social withdrawal, emotional detachment, cognitive deficits, and poverty of speech. Not only does schizophrenia cause personal suffering by the patient, it also severely affects the patient's occupational and social functions, so that often the patient must be institutionalized, which results in a high cost to society.

A leading hypothesis suggests that the positive symptoms of schizophrenia can be effectively treated by compounds that act as antagonists at certain dopamine receptors. Currently, five principal dopamine receptors (D₁–D₅) that have been identified. Antipsychotic efficacy has been most closely associated with blockade of the D2 class of dopamine receptors. The typical antipsychotic agents (eg. haloperidol) are effective in controlling the positive symptoms of schizophrenia but do not adequately treat the negative symptoms and also induce significant adverse events, principally extrapyramidal side effects, hyperprolactinemia, and tardive dyskinesia.

One approach to developing better antipsychotic agents, involves the identification of compounds that combine D2 receptor blockade with actions at other receptors. One such agent is clozapine.

Clozapine was the first drug identified as an “atypical” antipsychotic, i.e., a drug effective in treating both the positive and negative symptoms of schizophrenia. Additionally, it did not cause EPS and the other adverse events seen with classical, “typical” antipsychotics. Although clozapine is an effective drug, its utility in treating schizophrenia has been limited because of the clinical observation that 1–2% of treated patients developed a potentially fatal blood disorder. More recently, olanzapine has been widely accepted as an atypical antipsychotic with relatively few adverse events. Atypical antipsychotics like clozapine and olanzapine are D2 receptor antagonists and also interact with receptor subtypes for several neurotransmitters, including dopamine, serotonin, norepinephrine, histamine, and acetylcholine. It is believed that some of these additional receptor activities are responsible for the improved efficacy of the atypical antipsychotics and that the adverse events of these agents may be mediated by interactions with others. The success of the atypical antipsychotic drugs has inspired research to produce even more effective drugs for the treatment of schizophrenia that would have negligible instances of adverse events.

The present invention provides antipsychotic compounds and methods of using those compounds to treat psychotic disorders, in particular, schizophrenia and mood disorders, such as bipolar disorders. These compounds offer certain improvements and advantages over the antipsychotics currently in clinical use.

BRIEF SUMMARY OF THE INVENTION

One aspect of the present invention provides compounds of formula (I):

wherein,

-   -   A is an optionally benzo-fused five or six member aromatic ring         having zero to three hetero atoms independently selected from N,         O, and S;     -   Alk is (C₁₋₄) alkylene optionally substituted with OH, methoxy,         ethoxy, or F;     -   Ar is optionally substituted phenyl, naphthyl, monocyclic         heteroaromatic, or bicyclic heteroaromatic;     -   R¹ is hydrogen or (C₁₋₄) alkyl optionally substituted with OH,         OR³, or OCH₂CH₂OH,         -   wherein R³ is (C₁₋₂) alkyl;     -   R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, OR⁴,         SR⁴, NO₂, CN, COR⁴, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, NR⁵COR⁴, NR⁵SO₂R⁴,         or optionally substituted phenyl,         -   wherein         -   R⁴ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl,             benzyl, or optionally substituted phenyl,         -   R⁵ and R⁶ are independently hydrogen, (C₁₋₆) alkyl, or             optionally substituted phenyl;     -   Z is one or two substituents independently selected from         hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OR⁷,         SR⁷, NO₂, CN, COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁷, NR⁸R⁹, or         optionally substituted phenyl,         -   wherein         -   R⁷ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl,             benzyl, or optionally substituted phenyl,         -   R⁸ and R⁹ are independently hydrogen, (C₁₋₆) alkyl, or             optionally substituted phenyl;     -   and salts, solvates, and crystal forms thereof.

Another aspect of the present invention provides compounds of formula (Ia):

wherein,

-   -   Alk is (C₁₋₄) alkylene optionally substituted with OH;     -   Ar is optionally substituted phenyl, naphthyl, monocyclic         heteroaromatic, or bicyclic heteroaromatic;     -   R¹ is hydrogen or (C₁₋₄) alkyl;     -   R² is H, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl,     -   Z is one or two substituents independently selected from         hydrogen, or halogen, and salts, solvates, and crystal forms         thereof.

Another aspect of the present invention provides compounds of formula (Ib):

wherein,

-   -   Alk is (C₁₋₄) alkylene;     -   Ar is optionally substituted phenyl,     -   R¹ is hydrogen or (C₁₋₄) alkyl;     -   R² is H, or (C₁₋₆) alkyl;     -   Z is one or two substituents independently selected from         hydrogen, or halogen; and salts, solvates, and crystal forms         thereof.

Another aspect of the present invention provides compounds of formula (Ic):

wherein,

-   -   Alk is (C₁₋₄) alkylene optionally substituted with OH;     -   Ar is optionally substituted phenyl;     -   R¹ is hydrogen or (C₁₋₄) alkyl;     -   R² is H, (C₁₋₆) alkyl, halogen, or fluorinated (C₁₋₆) alkyl;     -   Z is one or two substituents independently selected from         hydrogen, or halogen; and salts, solvates, and crystal forms         thereof.

Another aspect of the present invention provides compounds of formula (Id):

wherein,

-   -   Alk is (C₁₋₄) alkylene;     -   Ar is optionally substituted phenyl;     -   R¹ is hydrogen or (C₁₋₄) alkyl;     -   R² is H, or (C₁₋₆) alkyl;     -   Z is one or two substituents independently selected from         hydrogen, or halogen; and salts, solvates, and crystal forms         thereof.

Another aspect of the present invention provides compounds of formula (Ie):

wherein,

-   -   Alk is (C₁₋₄) alkylene;     -   Ar is optionally substituted phenyl;     -   R¹ is hydrogen or (C₁₋₄) alkyl     -   R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, or CN;     -   Z is one or two substituents independently selected from         hydrogen, or halogen; and salts, solvates, and crystal forms         thereof.

Another aspect of the present invention is the novel intermediate compounds taught herein in the synthesis of compounds of formula (I).

Another aspect of the present invention is a novel process to intermediate compounds taught herein in the synthesis of compounds of formula (I).

Another aspect of the present invention is the use the compounds of formula (I) as dopamine D₂ antagonists, and their use in treating patients suffering from a psychotic condition or mood disorder, including for example schizophrenia and bipolar disorders.

Another aspect is the pharmaceutical formulations which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Terms and symbols used herein have meanings consistent with usage in contemporary chemical literature unless otherwise noted. For example, the term “(C₁₋₆) alkyl” includes saturated and unsaturated alkyl groups that may be branched straight chain or cyclic such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, —CH₂CH₂═CH₂, —CH₂CH═C(CH₃)₂, —CH₂C(═CH₂)CH₃, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, and the like. The term “(C₁₋₄) alkylene” refers to —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂—. The term “halogen” includes fluoro, chloro, bromo and iodo. The term “fluorinated (C₁₋₆) alkyl” refers to a (C₁₋₆) alkyl group which is substituted with one or more fluorines, such as, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, 1,1,1,3,3,3-hexafluoroprop-2-yl, and 6-fluorohexyl.

The term “optionally substituted phenyl” refers to a phenyl group which may be substituted with one to three substituents selected from hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OH, (C₁₋₆) alkoxy, (C₁₋₆) fluorinated alkoxy, (C₁₋₆) thioalkyl, (C₁₋₆) acyl, (C₁–C₄ alkyl)sulfonyl, OCF₃, NO₂, CN, carboxamido which may be substituted on the nitrogen by one or two (C₁₋₄) alkyl groups, and NH₂ in which one of the hydrogens may be replaced by a (C₁₋₄) alkyl group and the other hydrogen may be replaced by either a (C₁₋₄) alkyl group, a (C₁₋₆) acyl group, or a (C₁–C₄ alkyl)sulfonyl group. The term “(C₁₋₆) alkoxy” includes such groups as methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy, 2-pentoxy, 3-hexyloxy, and the like. The term “(C₁₋₆) alkylthio” includes such groups as methylthio, ethylthio, isopropylthio, sec-butylthio, tert-butylthio, 1-hexylthio, and the like. The term “(C₁₋₆) acyl” includes, for example, formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, hexanoyl, and the like. The term “(C₁–C₄ alkyl)sulfonyl” includes methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, 1-butanesulfonyl and the like.

The term “monocyclic heteroaromatic” refers to a five or six membered aromatic ring containing one to three heteroatoms selected from N, O, and S. Recognize that if one of the heteroatoms is O or S, the heteroaromatic ring must be a five membered ring and that any other heteroatoms contained therein must be N. Examples of such monocyclic heteroaromatic systems include furan, thiophene, pyridine, pyrimidine, thiazole, 1,2,3-triazole, and the like.

The term “bicyclic heteroaromatic” refers to a bicyclic aromatic system containing one to three heteroatoms selected from N, O, and S. Examples include indole, benzofuran, benzothiophene, quinoline, isoquinoline, indazole, benzothiazole, and the like.

The term “optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic” refers to phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic which may be substituted with one to three substituents selected from hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OH, (C₁₋₆) alkoxy, (C₁₋₆) fluorinated alkoxy, (C₁₋₆) thioalkyl, (C₁₋₆) acyl, (C₁–C₄ alkyl)sulfonyl, OCF₃, NO₂, CN, carboxamido which may be substituted on the nitrogen by one or two (C₁₋₄) alkyl groups, and NH₂ in which one of the hydrogens may be replaced by a (C₁₋₄) alkyl group and the other hydrogen may be replaced by either a (C₁₋₄) alkyl group, a (C₁₋₆) acyl group, or a (C₁–C₄ alkyl)sulfonyl group.

In the case of optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, O, and S, the two atoms of the aromatic ring which are fused to the adjoining seven member ring are constrained to both be carbon. If the aromatic ring contains two additional adjacent carbon atoms, a benzene ring may be fused to the aromatic ring at those two adjacent carbon atoms. Examples of optionally benzo-fused five or six member aromatic rings having zero to three hetero atoms independently selected from N, S, and O include benzene, pyridine, furan, pyrrole, thiophene, thiazole, oxazole, pyrazole, imidazole, 1,2,3-triazole, naphthylene, quinoline, isoquinoline, indole, benzofuran, benzothiophene, and the like.

The compounds of the present invention may, depending upon their structure and manner of synthesis and isolation, exist as a pharmaceutically acceptable solvate. These solvates include water, methanol, and ethanol. Solvated forms of the compounds of the present invention represent a further embodiment of the present invention.

The compounds of formula (I) can exist in optically isomeric forms, ie., stereoisomeric forms. That is, these compounds have a least one chiral, ie., asymmetric, center at the carbon atom of the piperazine ring to which “Alk” is attached. Such asymmetry gives rise to at least one pair of enantiomers. An equal mixture of enantiomers is known as a “racemic” mixture or a “racemate.” The representation of formula (I) is intended to represent each of those stereoisomers and mixtures thereof.

The terms “R” and “S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). Some of the compounds of formula (I) may have two or more chiral centers.

Some of the compounds of the present invention may also be isomeric with respect to one or more double bonds, which introduces geometric, i.e., cis and trans, isomers. A discussion of optical and geometric isomers can be found in standard organic chemistry text books such as March's Advanced Organic Chemistry, 5^(th) Ed., Chapter 4, Wiley-Interscience, John Wiley & Sons, Inc., New York (2001). Herein, when a compound of the present invention is named, or its structure presented, without an indication of asymmetric form, all of the possible asymmetric forms are intended This invention is not limited to any particular isomer but includes all possible individual isomers and racemates.

Preferred among the compounds of formula (I) are those wherein:

-   -   a) The aromatic ring A is selected from the group consisting of:

Preferred among the compounds of formula (I) are those wherein:

-   -   b) Alk is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—;

Another preferred embodiment among the compounds of formula (I) are those wherein:

-   -   c) Ar is optionally substituted phenyl furan, or thiophene;

Another preferred embodiment among the compounds of formula (I) are those wherein:

-   -   d) R¹ is hydrogen, methyl, or —CH₂CH₂—O—CH₂CH₂—OH;

Another preferred embodiment among the compounds of formula (I) are those wherein:

-   -   e) Z is hydrogen or halogen;

Another preferred embodiment among the compounds of formula (I) are those wherein:

-   -   f) The stereo configuration is “S” about the carbon of the         piperazine group bound to Alk.

Another preferred embodiment among the compounds of formula (I) are those wherein:

-   -   g) R² is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, or         halogen.

It is an aspect of this invention that any combination of these preferred embodiments are contemplated.

The compounds of formula (If) listed in Table 1 are of particular interest:

The stereo configuration is “S” about the carbon of the piperazine group bound to Alk unless otherwise indicated.

TABLE 1 Ex. No. E₁ E₂ E₃ Alk Ar R¹ R² Z  59 CH C S CH₂CH₂Ph H CH₃ H  61 CH C S CH₂Ph H CH₃ H  62 CH C S CH₂(4-OCH₂CH═C(CH₃)₂)Ph H CH₃ H  63 CH C S CH₂(3,4-OCH₂O—)Ph H CH₃ H  64 CH C S CH₂(3,4-diOCH₃)Ph H CH₃ H  65 CH C S CH₂(4-iPr)Ph H CH₃ H  66 CH C S CH₂(4-PhO)Ph H CH₃ H  67 CH C S CH₂(napthalen-2-yl) H CH₃ H  68 CH C S CH₂(napthalen-1-yl) H CH₃ H  69 CH C S CH₂(4-CH₃)Ph H CH₃ H  70 CH C S CH₂(3-CH₃)Ph H CH₃ H  71 CH C S CH₂(2-F)Ph H CH₃ H  72 CH C S CH₂(3-F)Ph H CH₃ H  73 CH C S CH₂(4-F)Ph H CH₃ H  74 CH C S CH₂(2-CF₃)Ph H CH₃ H  75 CH C S CH₂(2-OCH₃)Ph H CH₃ H  76 CH C S CH₂(3-OCH₃)Ph H CH₃ H  77 CH C S CH₂(4-OCH₃)Ph H CH₃ H  78 CH C S CH₂(3,4-diCl)Ph H CH₃ H  79 CH C S CH₂(indol-3-yl) H CH₃ H  80 CH C S CH₂(thiophen-2-yl) H CH₃ H  81 CH C S CH₂(benzo(b)thiophen-3-yl) H CH₃ H  82 CH C S CH₂(3-O-i-Pr)Ph H CH₃ H  83 CH C S (R)CH₂Ph H CH₃ H  84 CH C S CH₂(2,4-DiOCH₃)Ph H CH₃ H  85 CH C S CH₂(4-Cl)Ph H CH₃ H  86 CH C S CH₂(2-Cl)Ph H CH₃ H  87 CH C S CH₂(3-Cl)Ph H CH₃ H  88 CH C S CH₂(3,5-DiF)Ph H CH₃ H  89 CH C S CH₂(3-CF₃)Ph H CH₃ H  90 CH C S CH₂CH₂Ph CH₃ CH₃ H  92 CH C S CH₂Ph CH₃ CH₃ H  93 CH C S CH₂(4-O—CH₂CH═CH₂)Ph CH₃ CH₃ H  94 CH C S CH₂(pyridin-2-yl) CH₃ CH₃ H  95 CH C S (R)CH₂Ph CH₃ CH₃ H 100 CH C S CH₂(napthalen-2-yl) CH₃ CH₃ H 101 CH C S CH₂(napthalen-1-yl) CH₃ CH₃ H 102 CH C S CH₂(4-CH₃)Ph CH₃ CH₃ H 103 CH C S CH₂(3-CH₃)Ph CH₃ CH₃ H 104 CH C S CH₂(2-F)Ph CH₃ CH₃ H 105 CH C S CH₂(3-F)Ph CH₃ CH₃ H 106 CH C S CH₂(4-F)Ph CH₃ CH₃ H 107 CH C S CH₂(3-CF₃)Ph CH₃ CH₃ H 108 CH C S CH₂(2-CF₃)Ph CH₃ CH₃ H 109 CH C S CH₂(2-OCH₃)Ph CH₃ CH₃ H 110 CH C S CH₂(3-OCH₃)Ph CH₃ CH₃ H 111 CH C S CH₂(4-OCH₃)Ph CH₃ CH₃ H 112 CH C S CH₂(3,4-diCl)Ph CH₃ CH₃ H 113 CH C S CH₂(indol-3-yl) CH₃ CH₃ H 114 CH C S CH₂(thiophen-2-yl) CH₃ CH₃ H 115 CH C S CH₂(benzo(b)thiophen-3-yl) CH₃ CH₃ H 118 CH C S CH₂(2-Cl)Ph CH₃ CH₃ H 119 CH C S CH₂(3-Cl)Ph CH₃ CH₃ H 120 CH C S CH₂(4-Cl—Ph) CH₃ CH₃ H 121 CH C S CH₂(4-OPh)Ph CH₃ CH₃ H 122 CH C S CH₂(3-OPh)Ph CH₃ CH₃ H 123 CH C S CH₂(3-O-iPr)Ph CH₃ CH₃ H 124 CH C S CH₂(2,4-di OCH₃)Ph CH₃ CH₃ H 132 CH C S CH₂CH₂(2-pyridin-2-yl) H CH₃ H 133 CH C S CH₂CH₂(2-pyridin-4-yl) H CH₃ H 176 CH C S CH₂CH₂(4-F)Ph H CH₃ H 177 CH C S CH₂CH₂(3-F)Ph H CH₃ H 178 CH C S CH₂CH₂(2-F)Ph H CH₃ H 179 CH C S CH₂CH₂(4-OCH₃)Ph H CH₃ H 180 CH C S CH₂CH₂(3-OCH₃)Ph H CH₃ H 181 CH C S CH₂CH₂(2-OCH₃)Ph H CH₃ H 182 CH C S CH₂CH₂(4-F)Ph CH₃ CH₃ H 183 CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ H 184 CH C S CH₂CH₂(2-F)Ph CH₃ CH₃ H 185 CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ H 186 CH C S CH₂CH₂(3-OCH₃)Ph CH₃ CH₃ H 187 CH C S CH₂CH₂(2-OCH₃)Ph CH₃ CH₃ H 188 CH C S CH₂CH₂(2-pyridin-4-yl) CH₃ CH₃ H 189 CH C S CH₂CH₂(2-pyridin-3-yl) H CH₃ H 190 CH C S CH₂CH₂(2-pyridin-3-yl) CH₃ CH₃ H 191 CH C S CH₂CH₂(2-pyridin-2-yl) CH₃ CH₃ H 194 CH C S (CH₂)₄Ph H CH₃ H 195 CH C S (CH₂)₄Ph CH₃ CH₃ H 201 CH C S (CH₂)₃Ph H CH₃ H 202 CH C S (CH₂)₃Ph CH₃ CH₃ H 209 CH C S CH₂(4-Br)Ph H CH₃ H 210 CH C S CH₂(4-I)Ph H CH₃ H 211 CH C S CH₂(4-O—CH₂CH═CH₂)Ph H CH₃ H 212 CH C S CH₂(thiaphen-3-yl) H CH₃ H 213 CH C S CH₂(4-O-isoPropyl)Ph H CH₃ H 218 CH C S CH₂(4-Br)Ph CH₃ CH₃ H 219 CH C S CH₂(thiophen-3-yl) CH₃ CH₃ H 220 CH C S CH₂(4-I)Ph CH₃ CH₃ H 221 CH C S CH₂(4-O-isoPropyl)Ph CH₃ CH₃ H 236 CH C S CH₂(3,5-DiCH₃)Ph H CH₃ H 237 CH C S CH₂(4-O—CH₂C(═CH₂)CH₃)Ph H CH₃ H 238 CH C S CH₂(2-OEt)Ph H CH₃ H 239 CH C S CH₂(2-O—iPr)Ph H CH₃ H 240 CH C S CH₂(pyridin-2-yl) H CH₃ H 240a CH C S CH₂(3-OPh)Ph H CH₃ H 241 CH C S CH₂(4-O—CH₂CH═C(CH₃)₂)Ph CH₃ CH₃ H 242 CH C S CH₂(3,4-OCH₂O—)Ph CH₃ CH₃ H 243 CH C S CH₂(3,4-Di(OCH₃))Ph CH₃ CH₃ H 244 CH C S CH₂(4-O—CH₂C(═CH₂)CH₃)Ph CH₃ CH₃ H 245 CH C S CH₂(4-isoPropyl)Ph CH₃ CH₃ H 246 CH C S CH₂(3,5-Di(CH₃))Ph CH₃ CH₃ H 247 CH C S CH₂(2-OCH₂CH₃)Ph CH₃ CH₃ H 248 CH C S CH₂(4-Ph)Ph CH₃ CH₃ H 249 CH C S CH₂(2-O-isoPropyl)Ph CH₃ CH₃ H 387 CH C S CH₂CH₂(3-Cl)Ph H CH₃ H 388 CH C S CH₂CH₂(4-Cl)Ph H CH₃ H 389 CH C S CH₂CH₂(2-Cl)Ph H CH₃ H 390 CH C S CH₂CH₂(4-Cl)Ph CH₃ CH₃ H 391 CH C S CH₂CH₂(3-Cl)Ph CH₃ CH₃ H 392 CH C S CH₂CH₂(2-Cl)Ph CH₃ CH₃ H 393 CH C S CH₂CH₂(4-CF₃)Ph H CH₃ H 394 CH C S CH₂CH₂(2-CF₃)Ph H CH₃ H 395 CH C S CH₂CH₂(3-CF₃)Ph H CH₃ H 396 CH C S CH₂CH₂(4-CF₃)Ph CH₃ CH₃ H 397 CH C S CH₂CH₂(2-CF₃)Ph CH₃ CH₃ H 398 CH C S CH₂CH₂(3-CF₃)Ph CH₃ CH₃ H 399 CH C S CH₂CH₂(2,4-diF)Ph H CH₃ H 400 CH C S CH₂CH₂(2,4-diF)Ph CH₃ CH₃ H 401 CH C S CH₂CH₂(3-F)Ph H CH₃ 6F 402 CH C S CH₂CH₂(4-OCH₃)Ph H CH₃ 6F 403 CH C S CH₂CH₂(3-F)Ph H CH₃ 7F 404 CH C S CH₂CH₂(4-OCH₃)Ph H CH₃ 7F 405 CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ 6F 406 CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ 6F 407 CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ 7F 408 CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ 7F 411 CH C S CH₂CH₂(3-F)Ph H CH₂CH₃ 7F 412 CH C S CH₂CH₂(3-F)Ph CH₃ CH₂CH₃ 7F 413 CH C S CH₂CH₂(4-OCH₃)Ph H CH₂CH₃ 7F 414 CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₂CH₃ 7F 423 CH C S CH₂CH₂(2-napthalen-1-yl) H CH₃ H 425 CH C S CH₂CH₂(2-napthalen-1-yl) CH₃ CH₃ H 428 CH C S CH₂CH₂(2-napthalen-2-yl) H CH₃ H 429 CH C S CH₂CH₂(2-napthalen-2-yl) CH₃ CH₃ H 434 CH C S CH₂CH₂(2-furan-3-yl) H CH₃ H 435 CH C S CH₂CH₂(2-furan-3-yl) CH₃ CH₃ H 439 CH C S CH₂CH₂(2-thiophene-3-yl) H CH₃ H 440 CH C S CH₂CH₂(2-thiophene-3-yl) CH₃ CH₃ H 441 CH C S CH₂Ph H CH(CH₃)₂ H 442 CH C S CH₂CH₂Ph H CH(CH₃)₂ H 443 CH C S CH₂(2-OCH₃)Ph H CH(CH₃)₂ H 444 CH C S CH₂CH₂Ph CH₃ CH(CH₃)₂ H 444a CH C S CH₂Ph CH₃ CH(CH₃)₂ H 444b CH C S CH₂(2-OCH₃)Ph CH₃ CH(CH₃)₂ H 445 CH C S CH₂CH₂Ph H C(CH₃)₃ H 446 CH C S CH₂CH₂Ph CH₃ C(CH₃)₃ H 460 N C S CH₂CH₂Ph H CH₃ H 461 N C S CH₂CH₂Ph CH₃ CH₃ H 462 N C S CH₂Ph H CH₃ H 463 N C S CH₂(2-OCH₃)Ph H CH₃ H 464 N C S CH₂CH₂(4-OCH₃)Ph H CH₃ H 465 N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ H 466 N C S CH₂CH₂(4-F)Ph H CH₃ H 467 N C S CH₂CH₂(3-F)Ph H CH₃ H 468 N C S CH₂CH₂Ph H CH(CH₃)₂ H 469 N C S CH₂CH₂(4-OCH₃)Ph H CH(CH₃)₂ H 470 N C S CH₂Ph H CH(CH₃)₂ H 471 N C S CH₂CH₂(3-F)Ph H CH(CH₃)₂ H 472 N C S CH₂CH₂(4-F)Ph H CH(CH₃)₂ H 473 N C S CH₂Ph CH₃ CH₃ H 474 N C S CH₂(2-OCH₃)Ph CH₃ CH₃ H 475 N C S CH₂CH₂Ph CH₃ CH(CH₃)₂ H 476 N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH(CH₃)₂ H 477 N C S CH₂Ph CH₃ CH(CH₃)₂ H 478 N C S CH₂CH₂(4-F)Ph CH₃ CH₃ H 479 N C S CH₂CH₂(3-F)Ph CH₃ CH₃ H 480 N C S CH₂CH₂(3-F)Ph CH₃ CH(CH₃)₂ H 481 N C S CH₂CH₂(4-F)Ph CH₃ CH(CH₃)₂ H 484 N C S CH₂CH₂Ph H CH₂CH₂ H CH₂CH₃ 486 N C S CH₂CH₂Ph CH₃ CH₂CH₂ H CH₂CH₃ 491 N C S CH₂CH₂Ph H cyclopentyl H 492 N C S CH₂CH₂Ph CH₃ cyclopentyl H 493 N C S CH₂Ph H cyclopentyl H 494 N C S CH₂Ph CH₃ cyclopentyl H 495 N C S CH₂CH₂(3-OCH₃)Ph H cyclopentyl H 496 N C S CH₂CH₂(3-OCH₃)Ph CH₃ cyclopentyl H 497 N C S CH₂CH₂(4-OCH₃)Ph H cyclopentyl H 498 N C S CH₂CH₂(4-OCH₃)Ph CH₃ cyclopentyl H 501 N C S CH₂CH₂(4-OCH₃)Ph H CH₂CH₃ H 502 N C S CH₂CH₂(4-F)Ph H CH₂CH₃ H 503 N C S CH₂CH₂(3-F)Ph H CH₂CH₃ H 504 N C S CH₂CH₂(3-OCH₃)Ph H CH₂CH₃ H 506 N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₂CH₃ H 507 N C S CH₂CH₂(4-F)Ph CH₃ CH₂CH₃ H 508 N C S CH₂CH₂(3-F)Ph CH₃ CH₂CH₃ H 509 N C S CH₂CH₂(3-OCH₃)Ph CH₃ CH₂CH₃ H 512 N C S CH₂CH₂(3-F)Ph H CF₃ H 514 N C S CH₂CH₂(4-F)Ph H CF₃ H 516 N C S CH₂CH₂(3-OCH₃)Ph H CF₃ H 518 N C S CH₂CH₂(4-OCH₃)Ph H CF₃ H 520 N C S CH₂CH₂(3-OCH₃)Ph CH₃ CF₃ H 522 N C S CH₂CH₂(3-F)Ph CH₃ CF₃ H 524 N C S CH₂CH₂(4-OCH₃)Ph CH₃ CF₃ H 526 N C S CH₂CH₂(4-F)Ph CH₃ CF₃ H 533 C C S CH₂CH₂Ph H benzofused 9F 534 C C S CH₂CH₂Ph CH₃ benzofused 9F 535 C C S CH₂CH₂(4-OCH₃)Ph H benzofused 9F 537 C C S CH₂CH₂(3-OCH₃)Ph H benzofused 9F 539 C C S CH₂CH₂(3-F)Ph H benzofused 9F 541 C C S CH₂CH₂(4-F)Ph H benzofused 9F 543 C C S CH₂CH₂(4-OCH₃)Ph CH₃ benzofused 9F 545 C C S CH₂CH₂(3-OCH₃)Ph CH₃ benzofused 9F 547 C C S CH₂CH₂(3-F)Ph CH₃ benzofused 9F 549 C C S CH₂CH₂(4-F)Ph CH₃ benzofused 9F 568 CH C═CH CH CH₂CH₂(4-F)Ph H 2-CH₃ 8F 569 CH C═CH CH CH₂CH₂(4-F)Ph CH₃ 2-CH₃ 8F 570 CH C═CH CH CH₂CH₂(4-F)Ph H 2- 8F CH(CH₃)₂ 571 CH C═CH CH CH₂CH₂(4-F)Ph CH₃ 2- 8F CH(CH₃)₂ 572 CH C═CH CH CH₂CH₂(3-F)Ph H 2- H CH(CH₃)₂ 573 CH C═CH CH CH₂CH₂(3-F)Ph CH₃ 2- H CH(CH₃)₂ 575 CH CH═C CH CH₂CH₂Ph H 3-CH₃ H 576 CH CH═C CH CH₂CH₂Ph CH₃ 3-CH₃ H 577 CH CH═C CH CH₂CH₂(3-F)Ph H 3-CH₃ H 578 CH CH═C CH CH₂CH₂(3-F)Ph CH₃ 3-CH₃ H 580 CH C═CH CH CH₂CH₂Ph H 2-CH₃ H 581 CH C═CH CH CH₂CH₂Ph CH₃ 2-CH₃ H 585 CH CH═C CH CH₂Ph H 3-H 8Cl 586 CH CH═C CH CH₂CH₂Ph H 3-H 8Cl 587 CH CH═C CH CH₂CH₂Ph CH₃ 3-H 8Cl 588 CH CH═C CH CH₂Ph CH₃ 3-H 8Cl 594 N N NH CH₂CH₂Ph H CH(CH₃)₂ H 595 N N NH CH₂CH₂Ph CH₃ CH(CH₃)₂ H 598 CH C S (S,R)CH₂CH(OH)Ph H CH₃ H 599 CH C S (S,S)CH₂CH(OH)Ph H CH₃ H 600 CH C S (S,S)CH₂CH(OH)Ph CH₃ CH₃ H 601 N C S (S,R)CH₂CH(OH)Ph H CH(CH₃)₂ H 602 N C S (S,S)CH₂CH(OH)Ph H CH(CH₃)₂ H 603 N C S (S,S)CH₂CH(OH)Ph CH₃ CH(CH₃)₂ H 609 CH C═CH CH CH₂CH₂(4-OCH₃)Ph H 2-CF₃ 8F 610 CH C═CH CH CH₂CH₂(4-OCH₃)Ph CH₃ 2-CF₃ 8F 611 CH C═CH CH CH₂CH₂(4-F)Ph H 2-CF₃ 8F 612 CH C═CH CH CH₂CH₂(4-F)Ph CH₃ 2-CF₃ 8F Compound number corresponds to example number in the Examples section.

The compounds of formula (Ib) listed in Table 2 are of particular interest: The stereo configuration is “S” about the carbon of the piperazine group bound to Alk unless otherwise indicated.

TABLE 2 (Ib)

Ex No.: Alk-Ar R¹ R² Z 533 CH₂CH₂Ph H H 9F 534 CH₂CH₂Ph CH₃ H 9F 535 CH₂CH₂(4-OCH₃)Ph H H 9F 537 CH₂CH₂(3-OCH₃)Ph H H 9F 539 CH₂CH₂(3-F)Ph H H 9F 541 CH₂CH₂(4-F)Ph H H 9F 543 CH₂CH₂(4-OCH₃)Ph CH₃ H 9F 545 CH₂CH₂(3-OCH₃)Ph CH₃ H 9F 547 CH₂CH₂(3-F)Ph CH₃ H 9F 549 CH₂CH₂(4-F)Ph CH₃ H 9F Compound number corresponds to example number in the Examples section.

Since the compounds of this invention are basic in nature, they react with any of a number of inorganic and organic acids to form acid addition salts. For the therapeutic utility taught herein, the salt of the claimed compounds must be pharmaceutically acceptable. Acids commonly employed to form pharmaceutically acceptable salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromo-phenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, lactic acid, maleic acid, tartaric acid, and the like. For further details on pharmaceutically acceptable salts, see Journal of Pharmaceutical Science, 66,1 (1977). Salts that are not pharmaceutically acceptable may be used as intermediates to prepare other compounds of formula (I) or a pharmaceutically acceptable salt of compounds of formula (I) and are within the scope of the present invention. Particular pharmaceutically acceptable salts ate those formed with hydrochloric acid, sulfuric acid, or phosphoric acid.

The intermediates and final products described herein may be isolated and purified by the conventional techniques known to artisans of organic chemistry. For example, the well-known techniques of chromatography, recrystallization, distillation, and sublimation may be used singularly and sequentially.

General Synthetic Methods

Compounds of formula (I) of this invention can be prepared by several methods generally known in the art of organic chemistry. Starting materials, the preparation of which are not described, are commercially available or can be readily prepared by known techniques from commercially available starting materials.

As shown in Scheme 1, compounds of formula (I) may be conveniently prepared from compounds of formula (IIa), by removal of the protecting group “ProG” from the amine nitrogen of the seven-member ring of the tricyclic ring system. The methods for introducing and removing these protecting groups are known in the art. See T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., (1981). Examples of such ProG groups include benzyl, acetyl, t-butoxycarbonyl, methanesulfonyl, and the like.

As used herein, “Pg” represents either hydrogen or an amine protecting group ProG. For those examples in which Pg is an amine protecting group, the penultimate intermediate can be converted to the compound of formula (I) by removal of the protecting group. In the following text, for those intermediates containing a group Pg in which Pg is an amine protecting group, the protecting group may be removed to give the unprotected amine. Similarly, for those intermediates in which Pg is hydrogen, an amine protecting group may be incorporated into the intermediate.

Compounds of formula (IIb) in which R¹ is hydrogen can be converted to compounds of formula (IIc) in which R¹ is (C₁₋₄) alkyl optionally substituted with hydroxy, methoxy, ethoxy, or OCH₂CH₂OH. This transformation can be accomplished, as shown in Scheme Ia, by treatment of formula (IIb) with an alkylating agent. Alkylating agents include alkyl halides and alkyl sulfonate esters. Examples include methyl iodide, 1-bromobutane, 2-propyl methanesulfonate, and bromoethylmethyl ether. This reaction is usually performed in the presence of a base and solvent. The base can be either an organic base such as pyridine or diisopropylethylamine or an inorganic base such as potassium carbonate. Solvents include methanol, ethanol, THF, and DMF. This transformation can also be accomplished by reductive alkylation of the piperazine by treatment with an aldehyde or ketone under reducing conditions. Examples of suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, and the like. Suitable ketones include acetone, methylethylketone, and the like. Reductive alkylations are often performed under catalytic hydrogenation conditions. Other reducing agents include formic acid, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. This transformation can also be accomplished by acylation of the piperazine nitrogen to form an amide and reduction of the amide to yield the alkylated piperazine. Examples of acylating agents include acyl halides such as acetyl chloride, propionyl chloride, pivaloyl chloride, and cyclopropylcarbonyl chloride, carboxylic acid anhydrides such as formylacetic anhydride and acetic anhydride, and carboxylic acids in the presence of an activating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. The resulting amides may be reduced to the tertiary amines with reducing agents such as lithium aluminum hydride or borane.

As shown in Scheme 2, compounds of formula (II) may be prepared by reacting an appropriately substituted piperazine of formula (V) with a tricyclic intermediate of formula (IV). “LG” represents a leaving group examples of which include NH₂, halo, OY₁, or SY₁, wherein Y₁ is lower alkyl such as methyl, ethyl, or propyl or optionally substituted phenyl or OP(═O)R¹⁰. R¹⁰ can be morpholine. This reaction may conveniently be performed with heating in a solvent such as DMSO, toluene, DMF, and N-methylpyrrolidinone.

Alternatively, as shown in Scheme 3, tricyclic amide and thioamide intermediates of formula (VI) wherein X is O or S, respectively, can react with substituted piperazines of formula (V) to give corresponding compounds of formula (II). This reaction is conveniently performed in a polar solvent and may be performed in the presence or absence of a Lewis acid such as TiCl₄.

In Scheme 4, compounds of formula (VIb), wherein X is S, may be prepared from compounds of formula (VIa), wherein X is O, by treatment with a dehydrative thiolating agent in the presence of an inert solvent. Examples of such dehydrative thiolating agents include P₂S₅ and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide). For a description of Lawesson's reagent and its use, see M. P. Cava and M. I. Levinson, Tetrahedron, 41, 5061 (1985).

As shown in Scheme 5, tricyclic intermediates of formula (IV) can be prepared from the corresponding tricyclic amide and thioamide intermediates of formula (VI). O-alkylation of an amide of formula (VIa) (X═O) provides an iminoether of formula (IV) (LG=OY₁). Suitable alkylating agents include Meerwein's reagent and methyl fluorosulfonate. Iminothioethers of formula (IV), wherein LG is SY₁, may be prepared by S-alkylation of thioamides of formula (VIb) (X═S). Suitable alkylating agents include alkyl halides, alkyl sulfonates such as methyl trifluoromethanesulfonate, Meerwein's reagent and methyl fluorosulfonate. Reaction of an amide of formula (VIa) (X═O), with a dehydrative halogenating agent provides an iminohalide of formula (IV), wherein LG is a halo group. Suitable dehydrative halogenating agents include POCl₃, SOCl₂, PCl₃, PCl₅, PBr₃, PPh₃/Br₂, P(OPh)₃/I₂ and PPh₃/MeI.

Compounds of formula (IV) in which LG is NH₂, OY₁ or SY₁ may be prepared from compounds of formula (VI), wherein LG is halo, by reaction with a suitable nucleophile, such as ammonia, an alcohol, or a thiol to give compounds of formula (IV), wherein LG is NH₂, OY₁ or SY₁, respectively. This reaction may be conveniently performed in a solvent and under basic conditions.

As shown in Scheme 6, compounds of formula (II) may also be prepared by ring closure of an intermediate of formula (XIIIa). This reaction may be effected by treatment of an amide of formula (XIIIa) with an activating agent in the presence of an inert solvent. Examples of such activating agents include TiCl₄, POCl₃, P₂S₅, and Lawesson's reagent.

According to Scheme 7, compounds of formula (VIa), may be prepared by cyclization of an amine compounds of formula (XIIb) in which Y₂ is OY₇ or NY₈Y₉ wherein Y₇, Y₈ and Y₉ are independently, hydrogen or lower alkyl such as methyl, ethyl, or propyl.

As seen in Scheme 8, amines of formula (XIIIb) may be prepared from compounds of formula (XIIIc). The symbol Y₃ represents a group that may be converted to an amino group, such as NO₂, COOH, and NHCOOY₄, wherein Y₄ may be an optionally substituted alkyl such as, but not limited to, methyl, ethyl, 2-phenylethyl, t-butyl, 2-(trimethylsilyl)ethyl, 2,2,2-trichloroethyl, vinyl, allyl or optionally substituted benzyl group such as, but not limited to, benzyl, p-methoxybenzyl, p-nitrobenzyl, or diphenylmethyl.

If Y₃ is NO₂, treatment of compounds of formula (XIIIc) under reducing conditions will provide corresponding compounds of formula (XIIIb). Examples of such reducing conditions include catalytic hydrogenation conditions or SnCl₂. Compounds of formula (XIIIc), wherein Y₃ is NHCOOY₄, may be converted to the corresponding compounds of formula (XIIIb) under conditions that allow for removal of the COOY₄ group. If Y₄ is optionally substituted alkyl, such conditions may include hydrolysis under acidic or basic conditions. If Y₄ is optionally substituted benzyl, treatment under reducing conditions, preferably catalytic hydrogenation conditions, provides the corresponding compound of formula (XIIIb). If Y₄ is t-butyl, treatment with acid provides a compound of formula (XIIIb). If Y₄ is 2,2,2-trichloroethyl, reducing conditions, preferably zinc metal in acidic medium, yield a compound of formula (XIIIb). If Y₄ is 2-(trimethylsilyl)ethyl, treatment with fluoride ion yield a compound of formula (XIIIb).

Compounds of formula (XIIIb) may also be prepared by Curtius rearrangement of the correspondent compound of formula (XIIIc) in which Y₃ is COOH. The Curtius rearrangement occurs by thermal rearrangement of the acylazide of formula (XIIIc) in which Y₃ is CON₃ to yield the isocyanate of formula (XIIIc) in which Y₃ is NCO. This isocyanate may be hydrolyzed either directly or through the urethane in which Y₃ is NHCO₂Y₄, to yield the corresponding compound of formula (XIIIb).

According to Scheme 9, compounds of formula (IVa) in which LG is NH₂ may be prepared by cyclization of aminonitrile compounds of formula (XIIId).

According to Scheme 10, aminonitrile compounds of formula (XIIId) may be prepared from corresponding compounds of formula (XIIIe), in the manner described for Scheme 8. Alternatively, compounds of formula (XIIId) may be prepared by Curtius rearrangement under conditions also described for Scheme 8.

As shown in Scheme 11, compounds of formula (XIIIa), wherein all groups are defined as above, may be prepared from corresponding compounds of formula (XIIIf) in which Y₃ is a group that may be converted to an amino group.

According to Scheme 12, compounds of formula (XIIIf), wherein Y₃ is a group that may be converted to an amino group as defined above, and all other groups are as defined above, may be prepared by coupling a compound of formula (V) with a compound of formula (XIIIg). Such coupling reactions may be performed under conditions commonly employed to form amide bonds. Coupling reagents include dicyclohexylcarbodiimide (DCC), diphenylphosphorylazide (DPPA), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).

As shown in Scheme 13, compounds of formula (XIII) in which Y₃ may be NH₂ or a group that may be converted to an amino group as described above, Y₁₀ may be hydrogen, CN, COOY₇ or CONY₈Y₉, in which Y₇, Y₈, and Y₉ may independently be hydrogen or lower alkyl, or NY₈Y₉ is the group (XVI), may be prepared by reaction of compounds of formula (XIV) in which Y₁₁ may be a halo group or OSO₂CF₃ with compounds of formula (XVa). This reaction may be performed under basic conditions in a polar, aprotic solvent. Suitable bases include NaH, KH, potassium tert-butoxide, lithium hydroxide and cesium carbonate. Suitable solvents include DMF, N-methylpyrrolidinone, DMSO, and THF. The coupling of compounds of formula (XIV) with compounds of formula (XVa) to yield a compound of formula (XIII) may also be performed in the presence of a metal catalyst. Conditions for this transformation may be found in Hartwig, Angew. Chem. Int. Ed. (1998) 37, 2046–2067, Wolff, et al., Acc. Chem. Res. (1998), 31, 805–818, Yang and Buchwald, J. Organomet. Chem. (1999) 576, 125–146, U.S. Pat. No. 6,271,225, U.S. Pat. No. 6,455,542, and references cited therein.

Compounds of formula (XIV) may be prepared by methods known in the art.

Alternatively as shown in Scheme 14, compounds of formula (XIII) in which Y₃ may be NH₂ or a group that may be converted to an amino group as described above, Y₁₀ may be hydrogen, CN, COOY₇ or CONY₈Y₉, in which Y₇, Y₈, and Y₉ may independently be hydrogen or lower alkyl, or NY₈Y₉ is the group (XVI), and the other groups are defined as above, may also be prepared by reaction of compounds of formula (XIVa) with compounds of formula (XV) in which Y₁₂ may be a halo group or OSO₂CF₃. This reaction may be performed under basic conditions in a polar, aprotic solvent. Suitable bases include NaH, KH, potassium tert-butoxide, lithium hydroxide, and cesium carbonate. Suitable solvents include DMF, N-methylpyrrolidinone, DMSO, and THF. The coupling of compounds of formula (XIVa) with compounds of formula (XV) to yield a compound of formula (XIII) may also be performed in the presence of a metal catalyst. Conditions for this transformation may be found in Hartwig, Angew. Chem. Int. Ed. 37, 2046–2067, (1998), Wolff, et al., Acc. Chem. Res., 31, 805–818, (1998), and Yang and Buchwald, J. Organomet. Chem. 576, 125–146, (1999), and references cited therein.

Compounds of formula (XIVa) may be prepared by methods known in the art.

According to Scheme 15, a compound of formula (VIa) can also be prepared by cyclization of isocyanate (XIIIh) under acidic conditions. Isocyanate (XIIIh) may be prepared from compounds of formula (XIII) in which Y₁₀ is hydrogen and Y₃ is an amino group by reaction with formicacetic anhydride and dehydration of the resulting formamide with a dehydrating agent such as POCl₃ or P₂O₅. Isocyanate (XIIIh) may also be prepared from compounds of formula (XIII) in which Y₁₀ is hydrogen and Y₃ is COOH by Curtius rearrangement as described before. Alternatively, a compound of formula (IIb) may also be prepared by reaction urea (XIIIi) in the presence of a Lewis acid. Urea (XIIIi) may be prepared by reaction of isocyanate (XIIIh) with an amine of formula (V).

In Scheme 16, compounds of formula (VIc), the aromatic ring is thiazole, may be prepared by cyclization of intermediate of formula (XVIII) with a dehydrative thiolating agent such as P₂S₅ or Lawesson's reagent. Compounds of formula (VId), the aromatic ring is an oxazole ring, may be prepared by cyclization of intermediate of formula (XVIII) with a dehydrating agent such as P₂O₅ or PPh₃/Tf₂O.

According to Scheme 17, compounds of formula (XVIII) are prepared by acylation of an amine of formula (XIX). This reaction is usually performed by treatment of formula of (XIX) with an acid chloride, or acid anhydride in the presence of a base in an inert solvent. Methods for the synthesis of compounds of formula (XIX) are known in the art; see, for example, Hagishita, et al., Bioorg. Med. Chem., 5(7), 1433–1446, (1997).

As shown in Scheme 18, compounds of formula (VIe), the A ring is pyrazole, or (VIf) the A ring is pyrimidine, may also be prepared by reaction of compounds of formula (XX) with a substituted hydrazine or an amidine, respectively. Compounds of formula (XX) are prepared as described in Roma, et al., Farmaco, Ed. Sci., 38, 546–558 (1983).

Methods for the preparation of compounds of formula (XVb) and formula (XVc) are known in the art and vary depending on the nature of the aromatic ring A.

The skilled artisan will recognize that substituents R² and Z in the compounds of formula (I) may be present in the precursor molecules of formulas (XIV), (XIVa), (XVb), and (XVc). Alternatively, these substituents may be introduced at any convenient point during the synthesis either by replacement of a hydrogen (through, for example, an electrophilic aromatic substitution reaction) or by conversion of an existing substituent into the substituents present in the compounds of formula (I). Examples of electrophilic aromatic substitution reactions include halogenation, nitration, Friedel-Crafts acylation, and electrophilic trifluoromethylation under conditions described in the literature. Examples of conversion of an existing substituent into one present in the final compound include conversion of a Br substituent into a substituent such as SR¹¹ or COR¹¹ by metallation with an organolithium reagent and reaction with an electrophile such as R¹¹SSR¹¹ or R¹¹COOMe. R¹¹ maybe (C₁₋₆)alkyl, fluorinated (C₁₋₆)alkyl, benzyl, or optionally substituted phenyl” Additionally, a Br substituent can be converted to an optionally substituted aromatic ring by reaction with an optionally substituted phenylboronic acid in the presence of a palladium catalyst. Many other such functional group transformations are reported in the literature.

General methods and specific examples of the synthesis of these compounds can be found in the following references:

-   Chakrabarti, et al., J. Med. Chem., 23, 878–884; (1980), -   Chakrabarti, et al., J. Med. Chem., 23, 884–889; (1980), -   Chakrabarti, et al., J. Med. Chem., 25, 1133–1140; (1982), -   Chakrabarti, et al., J. Med. Chem., 32, 2573–2582; (1989), -   Liegeois, et al., J. Med. Chem., 36, 2107–2114; (1993), -   Liegeois and Delarge, U.S. Pat. No. 5,393,752 (1995); -   Chakrabarti and Hotten, Eur. Pat. Appl., EP 354781; (1990), -   Bolton, et al., PCT Int. Appl., WO 9700252; (1997), -   Chakrabarti, et al., Eur. Pat. Appl., EP 27390; (1981), -   Tehim, et al., U.S. Pat. No. 5,602,124 (1998); -   Tehim, et al., U.S. Pat. No. 5,824,676 (1998); -   Eilingsfeld and Swybold, Ger. Offen. DE 2713573; (1978), -   Gallemaers, et al., Tetrahedron Lett., 693–694; (1976), -   Durnow and Abele, Chem. Ber., 97, 3349–3353, (1964), -   Klempier, et al., J. Heterocyclic Chem., 29, 93–95, (1992).

In Scheme 19, compounds of formula (XVd) may be prepared by regioselectively nitrating 3-bromobenzothiophene compounds to afford the 2-nitro-3-bromobenzothiophene compounds of formula (XVe). Suitable nitrating conditions include nitric acid (optionally in the presence of another acid, such as trifluoroacetic acid, sulfuric acid, or acetic acid, or in the presence of an inert solvent such as dichloromethane or water), fuming nitric acid, or sidium nitrite in the presence of an acid. Displacement of the 3-bromo-group with cyanide can be accomplished using CuCN in the presence of a polar solvent like DMF or N-methylpyrrolidinone to give compounds of formula (XVf). Reduction of the nitro group to the amine can be accomplished by reducing agents such as SnCl₂/HCl, Zn/HOAc and Pd—C/H₂ to give compounds of formula (XVd) in which Pg is hydrogen. A protecting group may be subsequently introduced.

Compounds of formula (V) of this invention may be prepared from compounds of formula (XXIVb), as shown in Scheme 20, in which one of the nitrogens in the piperazine ring may be protected by an amine protecting group, by removal of this protecting group. In this equation, ProG₂ represents an amine protecting group. Examples of such ProG₂ groups include benzyl, acetyl, t-butoxycarbonyl, methanesulfonyl, and the like. Examples of additional ProG₂ groups and methods for the introduction and removal of such groups can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. (1981). In the subsequent text, Pg₂ represents either hydrogen or an amine protecting group ProG₂. In the following text, for those intermediates containing a group Pg₂ in which Pg₂ is an amine protecting group, the protecting group may be removed to give the unprotected amine. Similarly, for those intermediates in which Pg₂ is hydrogen, an amine protecting group may be incorporated into the intermediate. The methods for introducing and removing these protecting groups are known in the art.

According to Scheme 21, compounds of formula (XXIVa) of this invention may be prepared from compounds of formula (XXVa) by removal of the amine protecting group ProG₁. Examples of such ProG₁ amine protecting groups include benzyl, acetyl, t-butoxycarbonyl, methanesulfonyl, and the like. Examples of additional ProG₁ groups and methods for the introduction and removal of such groups can be found in T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981. It will be recognized that in some instances, in compounds of formula (XXVa), Pg₂ and ProG₁ may both be protecting groups that are removed under the same reaction conditions. In those cases, deprotection of this compound will yield compounds of formula (V) in which R¹ is hydrogen. In compounds of formula (XXIVa), if Pg₂ is an amine protecting group, ProG₂, then alkylation of formula (XXIVa) will yield compounds of formula (XXIV), in which R¹ is (C₁₋₄) alkyl optionally substituted with hydroxy, methoxy, ethoxy, or OCH₂CH₂OH.

In Scheme 22, compounds of formula (XXV), in which all groups are defined as above, may be prepared by reduction of either a ketopiperazine of formula (XXVI) or a diketopiperazine of formula XVI. Pg₁ represents either hydrogen, (C₁₋₄) alkyl optionally substituted with hydroxy, methoxy, ethoxy, or OCH₂CH₂OH, or an amine protecting group ProG₁. Suitable reducing agents for this transformation include lithium aluminum hydride and borane. Methods for the synthesis of ketopiperazines and diketopiperazines are known in the art.

Further, as shown in Scheme 23, compounds of formula (XXVb) in which Alk is —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂— may be prepared from a suitably protected 2-substituted piperazine of formula (XXVIII) by employing either a Heck coupling/reduction sequence or a hydroboration/Suzuki coupling sequence. In the Heck coupling/reduction sequence, reaction of formula (XXVIII) with an arylhalide or aryl triflate in the presence of a suitable metal catalyst provides the unsaturated aryl product of formula (XXIX). For a description of the Heck reaction and its application to organic synthesis see, Whitcombe, et al., Tetrahedron, 57, 7449–7476, (2001); Herrmann, Wolfgang A., App. Homogeneous Catal. Organomet. Compd., 2, 712–732, VCH, Weinheim, Germany (Editors: Cornils, Boy; Herrmann, Wolfgang A.), (1996); and references cited therein. Reduction of compounds of formula (XXIX) provides compounds of formula (XXVb), m=0–2. Suitable reducing conditions include catalytic hydrogenation.

The hydroboration/Suzuki coupling sequence represents a second method for converting compounds of formula (XXVIII) to compounds of formula (XXVb). Reaction of formula (XXVIII) with a borane HBZZ′, in which Z and Z′ are independently H, alkyl such as methyl, ethyl, propyl, or alkoxy such as methoxy, ethoxy, or propoxy provides an organoborane of formula (XXX). Suitable boranes HBZZ′ include, borane, trisiamylborane, catecholborane, and 9-borabicyclo[3,3,0]nonane (9-BBN). Reaction of formula (XXX) with an arylhalide or aryl triflate in the presence of a suitable catalyst provides compounds of formula (XXVb). For a description of the Suzuki reaction and its application to organic synthesis see, Miyaura and Suzuki, Chem. Rev., 95, 2457–2483, (1995), and references cited therein.

Compounds of formula (XXVIII)(m=0) may be prepared by the method described in Tsuda, et al., J. Org. Chem., 55, 3388–3390, (1990), and Uozumi, et al., J. Org. Chem., 58, 6826–6832, (1993).

In Scheme 24 compounds of formula (XXVIII) (m=1,2) may be prepared by an alkylation of formula (XXXI) with an allyl halide or a homoallyl halide and to give compounds of formula (XXXII) and reduction with lithium aluminum hydride to give compounds of formula (XXVIII) (m=1,2).

The skilled artisan will appreciate that many of the aforementioned reactions may be performed in any convenient order. Similarly, for those compounds that contain an asymmetric center, the skilled artisan will recognize that the aforementioned reactions may be performed either on pure isomers or on a mixture of isomers. The isomers may be separated at any convenient stage during the synthesis.

Pharmacological Activity

Compounds of the formula (I) have moderate to high binding affinity for multiple neurotransmitter receptors, and in particular, the dopamine receptors. Those skilled in neuropharmacology and related disciplines have recognized dopamine receptor binding activity as indicative of antipsychotic, in particular, antischizophrenic properties. See P. Seeman, et al., Nature, 261, 717–718 (1976); P. Seeman, Synapse, 1, 133 (1987); H. Howard, et al., 28, 39 (1993); and J. Schaus. Et al., Annual Reports in Medicinal Chemistry, 33, 1 (1998). Cloning studies have currently demonstrated five principal dopamine receptor subtypes that fall into two major classes, D₁-like and D₂-like. The D₁-like class includes the D₁ and D₅ subtypes, and the D₂-like class encompasses the D₂, D₃, and D₄ subtypes. Table 2 shows the relative binding affinity of selected compounds of formula (I) for the D₂ receptor. The experimental protocol for the assay generating this data is in the Example section below.

TABLE 3 Relative D₂ Receptor Binding Affinity For Compounds of Formula (I) Comp. Affinity No. K_(i)* 59 +++ 61 ++++ 69 +++ 70 ++++ 71 ++++ 72 +++ 75 ++++ 76 ++++ 77 +++ 80 ++++ 85 ++++ 87 +++ 88 ++++ 90 +++ 92 +++ 103 +++ 109 ++++ 119 +++ 176 +++ 177 +++ 178 +++ 179 ++++ 180 ++++ 181 +++ 182 +++ 183 +++ 184 +++ 185 +++ 186 ++++ 187 +++ 194 ++++ 195 +++ 212 ++++ 219 +++ 460 ++++ 461 +++ 594 ++++ 595 +++ *K_(i) is generally defined as the binding affinity constant (i.e., dissociation constant) of an unlabeled ligand in a radioligand-binding assay. See, for example, Neurotransmitter Receptor Binding, Second Edition, Eds H. I. Yamamura, S. J. Enna, and M. J. Kuhar, Raven Press (1985). *++++ = <10 nM; +++ = 10–100 nM; ++ = 100–1000 nM

Using the relative K_(i) scale of Table 3, clozapine has a ++ affinity and olanzapine has a +++ affinity. Thus, many of the compounds of formula (I) exhibit D₂ receptor affinity greater than both clozapine and olanzapine.

Like clozapine and olanzapine, the compounds of formula (I) also exhibit affinity for the 5-HT₆ receptor. Because clozapine and olanzapine have greater efficacy in treating the cognitive disturbances of schizophrenia than typical antipsychotics (Purdon, et al., Arch Gen. Psych., 57, 249 (2000)) and selective 5-HT₆ antagonists are active in models of cognitive enhancement, this activity is desirable in an antipsychotic drug.

Many atypical antipsychotics have a high affinity for the 5-HT_(2A) receptor. Researchers believe that high affinity for the 5-HT_(2A) receptor helps in treating the negative symptoms of schizophrenia and preventing some of the motor side effects (H Meltzer, et al., J. Pharm. Exp. Ther. 25, 238 (1989)). However, selective 5-HT_(2A) antagonists are not effective antipsychotics as monotherapy. Thus, 5-HT_(2A) antagonism would likely be among the other neuroreceptor affinities of a superior antipsychotic compound. The compounds of formula (I) exhibit a desirable level of 5-HT_(2A) affinity.

The compounds of formula (I) are useful for treating pathologic psychologic conditions, especially psychosis, with minimal detrimental adverse events. Pathologic psychological conditions which are psychosis or may be associated with psychotic features include, but are not limited to the psychotic disorders which have been characterized in the DSM-IV-TR., Diagnostic and Statistical Manual of Mental Disorders. Revised, 4^(th) Ed., Text Revision (2000). See also DSM-IV, Diagnostic and Statistical Manual of Mental Disorders 4^(th) Ed., (1994). The DSM-IV and DSM-IV-TR was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides descriptions of diagnostic categories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress. Examples of pathologic conditions associated with psychosis that may be treated with the compounds of the present invention include, but are not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, schizotypical, schizoid, paranoid personality disorder, and psychotic disorder-not other specified, see DSM-IV, Section: Schizophrenia and Other Psychotic Disorders, pages 273 to 316.

Compounds of the present invention are useful in treating depression and mood disorders found in the DSM-IV, Diagnostic and Statistical Manual of Mental Disorders 4^(th) Ed., (1994) Section: Mood Disorders, pages 317 to 392. Disorders include, but are not limited to, mood disorders such as major depressive episodes, manic episode, mixed episode, hypomanic episode; depressive disorders such as major depressive disorder, dysthymic disorder, depressive disorder not otherwise specificed; Bipolar disorders such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, bipolar disorder not otherwise specified; other mood disorders such as mood disorder due to general medical conditions, substance-induced mood disorder, mood disorder not otherwise specified; and mood disorders with mild, moderate, severe without psychotic features, severe with psychotic features, in partial remission, in full remission, with catatonic features, with melancholic features, with atypical features, with postpartum onset.

One of oridinary skilled in the art would appreciate that the compounds of the present invention would be useful in the treatment of depressive episodes associated with bipolar disorders, treatment of manic episodes associated with bipolar disorders such as, but not limited to, the treatment of the acute manic episodes associated with bipolar I disorder.

Compounds of the present invention are useful in treating cognitive disorders, age-related cognitive disorder, mild cognitive impairment, postconcussional disorder, mild neurocognitive disorder, anxiety (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), and migraine (including migraine headache). These compounds are also useful in treating substance withdrawal (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, caffeine, etc.). Other conditions that may be treated with the compounds of the present invention include, but are not limited to, dementia, dementia with behavioral disturbances, movement disorders, personality disorders, borderline personality disorder, pervasive development disoders, eating disorders, premenstrual dysphoric disorder, tic disorders, sexual dysfunction, delirium, emesis, substance related disorders, impulse-control disorders, postpsychotic depressive disorder of schizophrenia, simple deteriorative disorder (simple schizophrenia), minor depressive disorder, recurrent brief depressive disorder, and mixed anxiety-depresssive disorder

Compounds of the present invention are also useful in treating the cognitive deficients associated with the above listed, but not limited to, psychological conditions such as schizophrenia, mood disorders, and other psychotic disorders.

An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

The compounds of the present invention are effective over a wide dosage range, but the actual dose administered being dependent on the condition being treated. While the exact dose is administered according to the discretion of the attending health care professional, typically, in the treatment of adult humans, dosages of from 0.1 to 500 mg, preferably from 0.25 mg to 100 mg, most preferably 0.25 mg to 50 mg per day may be used. A once a day dosage is normally sufficient, although divided doses may be administered. For example, for the treatment of psychotic disorders a dose range of from 0.1 mg to 500 mg, preferably 0.25 mg to 100 mg, per day is suitable.

In choosing a suitable regimen for patients suffering from psychotic conditions, compositions containing compounds of formula (I) as an active ingredient may be formulated to provide quick, sustained or delayed release of the active ingredient after administration to the patient. Depending on the method of administration, compositions may be formulated as tablets, capsules, suspensions, or elixirs for oral use, or injection solutions or suppositories for parental use. Preferably the compositions are formulated in a unit dosage form, each dosage containing from 0.1 mg to 500 mg, more usually 0.25 mg to 100 mg, of the active ingredient.

A preferred formulation of the invention is a capsule or tablet comprising 0.1 to 500 mg of active ingredient together with a pharmaceutically acceptable carrier. A further preferred formulation is an injection which in unit dosage form comprises 0.1 mg to 500 mg of active ingredient together with a pharmaceutically acceptable diluent. A sustained release formulation is also a preferred formulation.

Pharmaceutical Formulations

While it is possible to administer a compound of formula (I) with no additional ingredients to a patient in need thereof, it is far more desirable to administer such a compound in the form of a pharmaceutical composition. Pharmaceutical compositions containing a compound of formula (I) as an active ingredient provides control of the dosage and rate of absorption into the body and stability of the product in shipment and storage. Further, pharmaceutical formulations are more acceptable to the patient being treated, and thus increase compliance with a treatment program. Such compositions, comprising at least one pharmaceutically acceptable carrier, are valuable and novel because of the presence of the compounds of formula (I) therein. Formulation of pharmaceutical compositions is an art unto itself, about which much has been published. The compounds of the present invention may be formulated into pharmaceutical compositions by essentially any suitable method of the art including, but not limited to, the methods discussed hereinbelow.

The usual methods of formulation used in pharmaceutical science and the usual types of compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches and suspensions. In general, compositions contain from about 0.5% to about 50% by weight of the compound in total, depending on the desired dose and the type of composition to be used. The amount of the compound, however, is best defined as the effective amount, that is, the amount of each compound which provides the desired dose to the patient in need of such treatment. The compositions may be chosen and formulated for convenience and economy. Any compound may be formulated in any desired form of composition. Some discussion of different compositions will be provided, followed by some typical formulations.

Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, naphth and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

Tablets are often coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established practice. Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.

When it is desired to administer the combination as a suppository, the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also.

Transdermal patches have become popular in recent years because of technological advances in matrix compositions. Typically they comprise a resinous matrix composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with pores through which the drugs are pumped by osmotic action.

EXAMPLES

The following examples illustrate aspects of this invention but should not be construed as limitations thereof. The symbols and conventions used in these examples and consistent with those used in the contemporary chemical literature such as the Journal of the American Chemical Society, and Tetrahedron Letters, and contemporary literature of other scientific disciplines as appropriate.

Chemical Compounds

Example 1 3-(S)-Phenethyl-piperazine-2,5-dione

Add sequentially, glycine methyl ester hydrochloride (4.51 g, 35.9 mmol), 1-ethyl-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (8.23 g, 42.9 mmol), 1-hydroxybenzotriazole monohydrate (5.81 g, 43.0 mmol), and triethylamine (10.0 mL, 71.7 mmol) to a solution of 2-tert-butoxycarbonylamino-4-(S)-phenyl-butyric acid (10.0 g, 35.8 mmol) in methylene chloride (30 mL) at 0° C. Stir the mixture at room temperature overnight and concentrate. Partition the residue between ethyl acetate and aqueous 2N HCl (100 mL). Wash the organic layer with 10% K₂CO₃, dry (MgSO₄), and concentrate to provide the (2-tert-butoxycarbonylamino-4-(S)-phenyl-butyrylamino)-acetic acid methyl ester as a clear oil (12.3 g, 98%): ¹H NMR (CDCl₃): δ1.45 (s, 9H), 1.95 (m, 1H), 2.20 (m, 1H), 2.71 (t, 2H), 3.76 (s, 3H), 4.04 (d, 2H), 4.16 (m, H), 5.00 (d, 1H), 6.57 (t, 1H), 7.17–7.32 (m, 5H).

Add trifluoroacetic acid (30 mL) to (2-tert-butoxycarbonylamino-4-(S)-phenyl-butyrylamino)-acetic acid methyl ester (14.4 g). Stir one hour at room temperature and concentrate to afford (2-amino-4-(S)-phenyl-butyrylamino)-acetic acid methyl ester trifluoroacetate as an amber oil: ¹H NMR (D₂O): δ2.09 (m, 2H), 2.67 (m, 2H), 3.61 (s, 3H), 3.82 (d, 1H), 3.91 (d, 1H), 3.95 (m, 1H), 7.13–7.28 (m, 5H).

Add methanol (200 mL) and Et₃N (30 mL) to the crude trifluoroacetate salt and reflux the solution. At 2 hours, white crystals begin to form. Reflux for an additional 2 hours and cool in an ice bath and filter. Wash the crystals with cold MeOH and hexanes to afford the title compound as white crystals (6.6 g, 74%): ¹H NMR (DMSO-d6): δ1.97 (m, 2H), 2.63 (m, 2H), 3.70 (d, 1H), 3.75 (m, 1H), 3.81 (d, 1H), 7.13–7.32 (m, 5H), 8.03 (bs, 1H), 8.32 (bs, 1H).

By the method of Example 1, the following compounds were prepared and isolated as the (S) isomer except where noted below:

No: ArAlk Data 2 CH₂(4-CH₃)Ph mp 252–253° C.; ¹H NMR(DMSO-d₆): δ2.27(s, 3H), 2.77(d, 1H), 2.81(dd, 1H), 3.04(dd, 1H), 3.34(d, 1H), 4.03(m, 1H), 7.04–7.10(m, 4H), 7.86(s, 1H), 8.12(s, 1H); MS(APCI)m/z(rel intensity)219(100). 3 CH₂(3-CH₃)Ph ¹H NMR(DMSO-d₆): δ2.22(s, 3H), 2.76(d, 1H), 2.80(dd, 1H), 3.00(dd, 1H), 3.32(d, 1H), 4.00(m, 1H), 6.91– 6.95(m, 2H), 7.03(d, 1H), 7.12(t, 1H), 7.88(s, 1H), 8.11(s, 1H); MS(APCI)m/z(rel intensity)219(100). 4 CH₂(2-F)Ph mp 227° C.; ¹H NMR(DMSO-d₆): δ2.99(m, 2H), 3.15(d, 1H), 3.36(dd, 1H), 4.00(m, 1H), 6.91–7.36(m, 4H), 7.88(s, 1H), 8.10(s, 1H); MS(APCI)m/z(rel intensity)223 (100). 5 CH₂(3-F)Ph ¹H NMR(DMSO-d₆): δ2.87(dd, 1H), 2.98(d, 1H), 3.06(dd, 1H), 3.42(d, 1H), 4.06(m, 1H), 6.93–7.04(m, 3H), 7.27(m, 1H), 7.92(s, 1H), 8.12(s, 1H); MS(APCI)m/z (rel intensity)223(100). 6 CH₂(4-F)Ph ¹H NMR(DMSO-d₆): δ2.87(dd, 1H), 2.88(d, 1H), 3.04(dd, 1H), 3.38(d, 1H), 4.02(m, 1H), 7.07(t, 2H), 7.14(dd, 2H), 7.87(s, 1H), 8.11(s, 1H); MS(APCI)m/z(rel intensity)223(100). 7 CH₂(2-Cl)Ph ¹H NMR(DMSO-d₆): δ.08(dd, 1H), 3.19(dd, 1H), 3.48(m, 2H), 3.99(m, 1H), 7.27–7.31(m, 3H), 7.43(m, 1H), 8.06(s, 2H); MS(APCI)m/z(rel intensity)239(100), 241 (36). 8 CH₂(3-Cl)Ph ¹H NMR(DMSO-d₆): δ2.90(dd, 1H), 3.06(d, 1H), 3.08 (dd, 1H), 3.49(d, 1H), 4.10(m, 1H), 7.15(m, 1H), 7.25(s, 1H), 7.32(m, 2H), 8.01(s, 1H), 8.22(s, 1H); MS(APCI) m/z(rel intensity)239(100), 241(36). 9 CH₂(4-Cl)Ph mp 259–262° C.; ¹H NMR(DMSO-d₆): δ2.89(dd, 1H), 3.01(d, 1H), 3.09(dd, 1H), 3.46(d, 1H), 4.08(m, 1H), 7.19(d, 2H), 7.35(d, 2H), 7.94(s, 1H), 8.17(s, 1H); MS (APCI)m/z(rel intensity)239(100), 241(36). 10 CH₂(3-CF₃)Ph ¹H NMR(DMSO-d₆): δ2.98(dd, 1H), 2.99(d, 1H), 3.16(dd, 1H), 3.46(d, 1H), 4.12(m, 1H), 7.43–7.60(m, 4H), 7.96(s, 1H), 8.20(s, 1H): ms(APCI)m/z(rel intensity) 273(100). 11 CH₂(2-CF₃)Ph ¹H NMR(DMSO-d₆): δ3.06(dd, 1H), 3.20(dd, 1H), 3.55(dd, 1H), 3.77(d, 1H), 3.89(m, 1H), 7.41–7.46(m, 2H), 7.59(t, 1H), 7.67(d, 1H), 8.03(s, 1H), 8.09(s, 1H); MS (APCI)m/z(rel intensity)273(100). 12 CH₂(2-OCH₃)Ph mp 222–224° C.: ¹H NMR(DMSOd₆): δ2.90(dd, 1H), 3.06(dd, 1H), 3.21(d, 1H), 3.41(d, 1H), 3.75(s, 3H), 3.93(m, 1H), 6.86(t, 1H), 6.95(d, 1H), 7.09(d, 1H), 7.24(t, 1H), 7.87(s, 1H), 7.92(s, 1H); MS(APCI)m/z(rel intensity)235(100). 13 CH₂(3-OCH₃)Ph mp 204–206° C.; ¹H NMR(DMSO-d₆): δ2.86(dd, 1H), 2.86(d, 1H), 3.07(dd, 1H), 3.38(d, 1H), 3.41(s, 3H), 4.05(m, 1H), 6.73(d, 1H), 6.74(s, 1H), 6.83(d, 1H), 7.19(t, 1H), 7.91(s, 1H), 8.13(s, 1H); MS(APCI)m/z(rel intensity)235(100). 14 CH₂(4-OCH₃)Ph ¹H NMR(DMSO-d₆): δ2.73(d, 1H), 2.75(dd, 1H), 2.97(dd, 1H), 3.31(d, 1H), 3.68(s, 3H), 3.96(m, 1H), 6.79(d, 2H), 7.02(d, 2H), 7.82(s, 1H), 8.06(s, 1H); MS(APCI) m/z(rel intensity)235(100). 15 CH₂(3,5-diCl)Ph ¹H NMR(DMSO-d₆): δ2.86(dd, 1H), 3.04(dd, 1H), 3.20(d, 1H), 3.50(d, 1H), 4.07(m, 1H), 7.14(d, 1H), 7.39(s, 1H), 7.51(d, 1H), 7.97(s, 1H), 8.15(s, 1H); MS(APCI) m/z(rel intensity)273(100), 275(60). 16 CH₂(indol-3yl) mp 262–271° C.; ¹H NMR(DMSO-d₆): δ2.74(d, 1H), 2.98(dd, 1H), 3.19(dd, 1H), 3.21(d, 1H), 3.98(m, 1H), 6.93(t, 1H), 7.02(t, 1H), 7.03(s, 1H), 7.29(d, 1H), 7.50(d, 1H), 7.72(s, 1H), 8.05(s, 1H); MS(APCI)m/z(rel intensity)244(100). 17 CH₂(thiophen-2-yl) ¹H NMR(DMSO-d₆): δ3.00(dd, 1H), 3.07(d, 1H), 3.28(dd, 1H), 3.45(d, 1H), 4.05(t, 1H), 6.80(s, 1H), 6.91(d, 1H), 7.40(d, 1H), 7.91(s, 1H), 8.17(s, 1H); MS(APCI) m/z(rel intensity)211(100). 18 CH₂(benzo(b)thiophen-3-yl) ¹H NMR(DMSO-d₆): δ3.04(d, 1H), 3.17(dd, 1H), 3.29(dd, 1H), 3.37(d, 1H), 4.08(s, 1H), 7.30–7.36(m, 2H), 7.37(s, 1H), 7.80(d, 1H), 7.87(s, 1H), 7.92(d, 1H), 8.15(s, 1H); MS(APCI)m/z(rel intensity)261(100). 20 CH₂(naphthalene-1-yl) ¹H NMR(DMSO-d₆): δ3.11(d, 1H), 3.35(d, 1H), 3.44(dd, 1H), 3.50(dd, 1H), 4.07(m, 1H), 7.37(d, 1H), 7.44(t, 1H), 7.48–7.57(m, 2H), 7.84(d, 1H), 7.92(d, 1H), 7.94(s, 1H), 8.10(s, 1H), 8.13(d, 1H); MS(APCI)m/z(rel intensity)255(100). 21 CH₂(naphthalene-2-yl) ¹H NMR(DMSO-d₆): δ2.83(d, 1H), 3.09(dd, 1H), 3.26(dd, 1H), 3.36(d, 1H), 4.16(m, 1H), 7.36(d, 1H), 7.45–7.52(m, 2H), 7.69(s, 1H), 7.80–7.91(m, 4H), 7.95(s, 1H), 8.27(s, 1H); MS(APCI)m/z(rel intensity)255 (100). 23 CH₂(3,5-Di-F)Ph ¹H NMR(DMSO-d₆): δ2.90(dd, 1H), 3.23(d, 1H), 3.52(d, 1H), 3.61(dd, 1H), 4.09(m, 1H), 6.86(d, 2H), 7.07(t, 1H), 8.00(s, 1H), 8.13(s, 1H); MS(APCI)m/z(rel intensity)241(100). 23a CH₂(4-Ph)Ph ¹H NMR(DMSO-d₆)δ2.94(dd, 1H), 3.06–3.18(m, 2H), 3.43(d, 1H), 4.11(m, 1H), 7.23(d, 2H), 7.36(t, 1H), 7.44(t, 2H), 7.61(d, 2H), 7.66(d, 2H), 7.94(bs, 1H), 8.20(bs, 1H).

Example 24 2-(S)-Phenethyl-piperazine

Add 3-(S)-phenethyl-piperazine-2,5-dione (2.5 g, 11 mmol) portionwise to lithium aluminum hydride (1.75 g, 46 mmol) in THF (46 mL). Reflux the resulting suspension for an hour and cool to 0° C. Add sodium sulfate decahydrate carefully until hydrogen evolution ceases and stir the mixture for an additional three hours at room temperature and filter. Wash the solids with THF several times. Combine the filtrates, concentrate, and recrystallize the residue with THF/pentane to afford 2-(S)-phenethyl-piperazine as white crystals (1.9 g, 90%): mp 114–115° C.; ¹H NMR (CDCl₃): δ1.58–1,70 (m, 2H), 2.41 (dd, 1H), 2.58–3.02 (m, 8H), 7.16–7.30 (m, 5H); MS (APCI) m/z (rel intensity) 191 (100).

By a similar method to Example 24, using the appropriate starting materials, the following piperazines were prepared and isolated as the (S) isomer except where noted below:

No: ArAlk Data 25 CH₂Ph mp 65–67° C.; ¹H NMR(CDCl₃): δ2.47–2.57(m, 2H), 2.67– 3.00(m, 7H), 7.16–7.30(m, 5H); MS(APCI)m/z(rel intensity) 177(100). 26 CH₂(4-Ph)Ph mp 129–134° C.; ¹H NMR(CDCl₃)δ2.51–2.59(m, 2H), 2.68– 3.03(m, 7H), 7.23(d, 2H), 7.31(t, 1H), 7.42(t, 2H), 7.57(d, 2H), 7.59(d, 2H); MS(ESIpos)m/z(rel intensity)253.3(100). 33 CH₂(naphthalen-1-yl) ¹H NMR(CDCl₃): δ2.58–2.67(m, 2H), 2.82(ddd, 1H), 2.85– 2.95(m, 3H), 3.02(m, 1H), 3.05(m, 1H), 3.22(dd, 1H), 7.37– 7.43(m, 2H), 7.47–7.54(m, 2H), 7.75(d, 1H), 7.86(m, 1H), 8.07(m, 1H); MS(APCI)m/z(rel intensity)227(100). 34 CH₂(naphthalen-2-yl) ¹H NMR(CDCl₃): δ2.57(dd, 1H), 2.65–2.99(m, 7H), 3.02(dd, 1H), 7.33(d, 1H), 7.42–7.50(m, 2H), 7.66(s, 1H), 7.75– 7.83(m, 3H); MS(APCI)m/z(rel intensity)227(100). 35 CH₂(3-F)Ph ¹H NMR(CDCl₃): δ2.57–2.46(ddd, 1H), 2.81–2.65(m, 4H), 3.02–2.82(m, 4H), 7.00–6.88(m, 3H), 7.29–7.21(m, 1H); MS (APCI)m/z(rel intensity)195.3(100). 36 CH₂(2-F)Ph ¹H NMR(CDCl₃): δ2.49(dd, 1H), 2.58(dd, 1H), 2.98–2.84(m, 3H), 3.02–2.82(m, 4H), 7.09–6.97(m, 2H), 7.24–7.17(m, 2H); MS(APCI)m/z(rel intensity)195.3(100). 37 CH₂(3-CF₃)Ph ¹H NMR(CDCl₃): δ2.50(dd, 1H), 2.61(dd, 1H), 2.81–2.69(m, 3H), 2.98–2.83(m, 4H), 7.54–7.36(m, 4H); MS(APCI) m/z(rel intensity)245.3(100). 38 (R)—CH₂Ph ¹H NMR(CDCl₃): δ2.47–2.57(m, 2H), 2.67–3.00(m, 7H), 7.16–7.30(m, 5H); MS(APCI)m/z(rel intensity)177(100). 39 CH₂(3-CH₃)Ph mp 58–63° C.; ¹H NMR(CDCl₃): δ2.33(s, 3H), 2.50(ddd, 2H), 2.67(dd, 1H), 2.94–2.70(m, 5H), 2.98(dd, 1H), 7.06– 6.97(m, 3H), 7.19(t, 1H); MS(APCI)m/z(rel intensity)191.3 (100). 40 CH₂(indol-3-yl) mp 45–58° C.; ¹H NMR(CDCl₃): δ2.54(dd, 1H), 3.02–2.63(m, 7H), 3.06(dd, 1H), 7.05(bs, 1H), 7.11(dt, 1H), 7.18(dt, 1H), 7.36(dd, 1H), 7.65(d, 1H), 8.06(bs, 1H) 41 CH₂(benzo(b)thiophen-3-yl) ¹H NMR(CDCl₃): δ2.57(dd, 1H), 2.99–2.76(m, 7H), 3.08(dd, 1H), 7.15(s, 1H), 7.19(s, 1H), 7.35–7.25(m, 1H), 7.82– 7.70(m, 2H), MS(APCI)m/z(rel intensity)233.2(100). 42 CH₂(4-F)Ph ¹H NMR(CDCl₃): δ2.46(ddd, 2H), 2.63(dd, 1H), 2.84–2.67(m, 3H), 2.95–2.85(m, 3H), 6.98–6.92(m, 2H), 7.14–7.04(m, 2H); MS(APCI)m/z(rel intensity)195.3(100). 43 CH₂(4-OCH₃)Ph mp 76–80° C.; ¹H NMR(CDCl₃): δ2.45(ddd, 2H), 2.61(dd, 1H), 2.82–2.65(m, 3H), 2.91–2.85(m, 2H), 2.94(dd, 1H), 3.76(s, 3H), 6.81(d, 2H), 7.09(d, 2H); MS(APCI)m/z(rel intensity)207.3(100). 46 CH₂(4-CH₃)Ph mp 64–68° C.; ¹H NMR(CDCl₃): δ2.32(s, 3H), 2.47(dd, 1H), 2.49(dd, 1H), 2.65(dd, 1H), 2.68(dd, 1H), 2.73(dd, 1H), 2.80(m, 1H), 2.86–2.93(m, 2H), 7.07–7.13(m, 4H); MS(APCI) m/z(rel intensity)191(100). 47 CH₂(4-Cl)Ph mp 77–81° C.; ¹H NMR(CDCl₃): δ2.45(ddd, 2H), 2.61(dd, 1H), 2.82–2.65(m, 3H), 2.91–2.85(m, 2H), 2.94(dd, 1H), 6.81(d, 2H), 7.09(d, 2H); MS(APCI)m/z(rel intensity)211.3 (100). 48 CH₂(2-OCH₃)Ph ¹H NMR(CDCl₃): δ2.49(dd, 1H), 2.53(dd, 1H), 2.80–2.68(m, 3H), 2.98–2.87(m, 4H), 3.81(s, 3H), 6.90–6.83(m, 2H), 7.23–7.12(m, 2H); MS(APCI)m/z(rel intensity)207.3(100). 49 CH₂(3-OCH₃)Ph mp 57–61° C.; ¹H NMR(CDCl₃); δ2.49(dd, 1H), 2.52(dd, 1H), 2.78–2.65(m, 3H), 2.94–2.79(m, 3H), 2.97(dd, 1H), 3.80(s, 3H), 6.81–6.74(m, 3H), 7.21(ddd, 1H); MS(APCI)m/z(rel intensity)207.3(100). 50 CH₂(2-Cl)Ph ¹H NMR(CDCl₃): δ2.53(dd, 1H), 2.65(dd, 1H), 2.81–2.70(m, 2H), 2.99–2.83(m, 5H), 7.27–7.14(m, 3H), 7.38–7.35(m, 1H); MS(APCI)m/z(rel intensity)211(100), 213(36). 51 CH₂(3-Cl)Ph ¹H NMR(CDCl₃): δ2.49(dd, 1H), 2.51(dd, 1H), 2.67(m, 1H), 2.77–2.71(m, 2H), 2.99–2.78(m, 4H), 7.10–7.07(m, 1H), 7.26–7.19(m, 3H); MS(APCI)m/z(rel intensity)211(100), 213(38). 52 CH₂(3,4-Di-Cl)Ph ¹H NMR(CDCl₃): δ2.49(dd, 1H), 2.97–2.73(m, 7H), 3.00(dd, 1H), 6.86–6.83(m, 1H), 6.94(dd, 1H), 7.17(dd, 1H); MS (APCI)m/z(rel intensity)245(100). 53 CH₂(thiophen-2-yl) ¹H NMR(CDCl₃): δ2.49(dd, 1H), 2.51(dd, 1H), 2.67(m, 1H), 2.77–2.71(m, 2H), 2.99–2.78(m, 4H), 7.10–7.07(m, 1H), 7.26–7.19(m, 2H); MS(APCI)m/z(rel intensity)183(100). 55 CH₂(2-CF₃)Ph ¹H NMR(CDCl₃): δ2.53–2.46(m, 1H), 2.78–2.66(m, 3H), 2.96–2.84(m, 5H), 7.31(t, 1H), 7.37(d, 1H), 7.46(t, 1H), 7.63(d, 1H): MS(APCI)m/z(rel intensity)183(100). 57 CH₂(3,5-Di-F)Ph ¹H NMR(CDCl₃): δ2.48(ddd, 1H), 2.53(dd, 1H), 2.66(dd, 1H), 2.72–2.78(m, 2H), 2.84(m, 1H), 2.88–2.98(m, 3H), 6.67(t, 1H), 6.73(d, 2H); MS(APCI)m/z(rel intensity)213(100).

Example 58 2-(S)-(4-Bromo-benzyl)-pipierazine

Add dropwise a 1M solution of BH₃.THF (183 mL, 183 mmol) to 3-(S)-(4-bromo-benzyl)-piperazine-2,5-dione (6.5 g, 23 mmol) in 100 mL of dry THF at ambient temperature. Stir for an hour then heat to reflux for two days and cool down to 0° C. Add slowly a 12% hydrobromic acid solution in acetic acid and stir overnight. Isolate the precipitate, wash it with ethyl acetate and hexanes and dry it to yield the di-hydrobromic salt as a white solid. Add to this solid a saturated sodium bicarbonate in water and extract with a solution of dichloromethane and isopropyl alcohol (75/25). Dry over magnesium sulfate and evaporate the solvent to yield the title compound (4.3 g, 73%) as a white powder: mp=91–93° C.; ¹H NMR (CDCl₃): δ2.45–2.52 (m, 2H), 2.64 (dd, 1H), 2.68–2.75 (m, 2H), 2.82 (m, 1H), 2.88–2.97 (m, 3H), 7.08 (d, 2H), 7.42 (d, 2H); MS (APCI) m/z (rel intensity) 255 (100), 257 (100).

Example 59 2-Methyl-10-(S)-(3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene

Heat a suspension of 2-methyl-4H-3-thia4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride (466 mg, 1.75 mmol) and 2-(S)-phenethyl-piperazine (1.0 g, 5.3 mmol) in DMSO (2.5 mL) and toluene (10 mL) at reflux for 48 hours. Evaporate the toluene under vacuo and pour the resulting solution into water (10 mL). Purify the resulting brown solid by flash chromatography eluting with methylene chloride/methanol (95:5) to give 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene as a yellow solid (478 mg, 65%): mp 75–84° C.; ¹H NMR(CDCl₃): δ1.76 (m, 2H), 2.31 (s, 3H), 2.60 (dd, 1H), 2.71 (m, 2H), 2.80 (m, 1H), 2.92 (m, 2H), 3.04 (m, 1H), 3.96 (m, 1H), 4.12 (m, 1H), 4.91 (s, 1H), 6.29 (s, 1H), 6.60 (d, 1H), 6.89 (t, 1H), 6.96 (t, 1H), 7.03 (d, 1H), 7.15–7.30 (m, 5H); MS (APCI) m/z (rel intensity) 403 (100).

By a method similar to Example 59, using the appropriate starting material, the following compounds were prepared and isolated as the (S) isomer except where noted below:

No: ArAlk Data 61 CH₂Ph mp 169–170° C.; ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.61(dd, 1H), 2.68(dd, 1H), 2.71–2.87(m, 2H), 2.92–3.03(m, 3H), 3.99(d, 1H), 4.09(d, 1H), 4.93(s, 1H), 6.20(s, 1H), 6.59(d, 1H), 6.87(t, 1H), 6.96(t, 1H), 7.03(d, 1H), 7.20–7.33(m, 5H); MS (APCI)m/z(rel intensity)389(100). 70% yield. 62 CH₂(4-O—CH₂CH═C(CH₃)₂)_(Ph) mp 86–97° C.; ¹H NMR(CDCl₃)δ1.74(s, 3H), 1.80(s, 3H), 2.26(s, 3H), 2.57(dd, 1H), 2.67(dd, 1H), 2.74(dd, 1H), 2.84(dd, 1H), 3.04–2.92(m, 3H), 4.00(d, 1H), 4.08(d, 1H), 4.49(d, 2H), 4.95(s, 1H), 5.50(m, 1H), 6.20(d, 1H), 6.60(dd, 1H), 6.89–6.84(m, 3H), 6.96(dt, 1H), 7.02(dd, 1H), 7.13(d, 2H); MS(APCI)m/z(rel intensity)473.5(100). 34% yield. 63 CH₂(3,4-OCH₂O—)Ph mp 123–130° C.; ¹H NMR(CDCl₃)δ2.26(s, 3H), 2.55(dd, 1H), 2.67(dd, 1H), 2.72(dd, 1H), 2.85(dd, 1H), 3.04–2.92(m, 3H), 4.00(d, 1H), 4.08(d, 1H), 4.98(s, 1H), 5.94(d, 2H), 6.21(dd, 1H), 6.61(dt, 1H), 6.68(dt, 1H), 6.77–6.73(m, 2H), 6.87(ddd, 1H), 6.97(ddd, 1H), 7.02(dd, 1H); MS(APCI)m/z(rel intensity)433.5(100). 43% yield. 64 CH₂(3,4-Di-OCH₃)Ph mp 127–139° C.; ¹H NMR(CDCl₃)δ2.26(s, 3H), 2.55(dd, 1H), 2.68(dd, 1H), 2.76(dd, 1H), 2.82(dd, 1H), 3.04–2.92(m, 3H), 3.87(s, 3H), 3.88(s, 3H), 4.00(d, 1H), 4.15(d, 1H), 4.98(s, 1H), 6.22(d, 1H), 6.60(dd, 1H), 6.83–6.73(m, 3H), 6.87(dt, 1H), 6.97(dt, 1H), 7.02(dd, 1H); MS(APCI)m/z(rel intensity) 449.5(100). 47% yield. 65 CH₂(4-iPr)Ph mp 78–83° C.: ¹H NMR(CDCl₃)δ1.24(d, 6H), 2.27(s, 3H), 2.57(dd, 1H), 2.69(dd, 1H), 2.76(dd, 1H), 2.79–3.02(m, 5H), 3.98(m, 1H), 4.11(m, 1H), 4.97(s, 1H), 6.23(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.01(d, 1H), 7.14–7.18(m, 4H); MS(APCI)m/z(rel intensity)431(100). 66% yield. 66 CH₂(4-OPh)Ph ¹H NMR(CDCl₃)δ2.27(s, 3H), 2.61(dd, 1H), 2.67(dd, 1H), 2.76(dd, 1H), 2.86(ddd, 1H), 2.93–3.05(m, 3H), 3.99(m, 1H), 4.09(m, 1H), 4.96(s, 1H), 6.22(s, 1H), 6.59(d, 1H), 6.86(t, 1H), 6.94–7.02(m, 5H), 7.10(t, 1H), 7.19(d, 2H), 7.33(t, 2H); MS(APCI)m/z(rel intensity)481(100). Product isolated as an orange powder. 67 CH₂(naphthalene-2-yl) mp 101–119° C.; ¹H NMR(CDCl₃): δ2.32(s, 3H), 2.70–2.88(m, 3H), 2.98(m, 3H), 3.10(m, 1H), 4.00(m, 1H), 4.17(m, 1H), 4.93(s, 1H), 6.28(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.02(d, 1H), 7.39(d, 1H), 7.32(m, 2H), 7.70(s, 1H), 7.81(m, 3H); MS(APCI)m/z(rel intensity)439(100). 27% yield. 68 CH₂(naphthalene-1-yl) mp 106–116° C.; ¹H NMR(CDCl₃): δ2.30(s, 3H), 2.74–2.83(m, 2H), 2.94–3.06(m, 3H), 3.18(m, 1H), 3.30(dd, 1H), 3.96(m, 1H), 4.15(m, 1H), 4.92(s, 1H), 6.14(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 7.96(t, 1H), 7.03(d, 1H), 7.40(m, 2H), 7.47–7.56(m, 2H), 7.77(d, 1H), 7.88(d, 1H), 8.09(d, 1H); MS(APCI) m/z(rel intensity)439(100). 36% yeild. 69 CH₂(4-CH₃)Ph mp 92–101° C.; ¹H NMR(CDCl₃): δ2.26(d, 3H), 2.33(s, 3H), 2.57(dd, 1H), 2.68(dd, 1H), 2.86–2.74(m, 2H), 3.03–2.91(m, 3H), 4.00(bd, 1H), 4.10(bd, 1H), 4.97(s, 1H), 6.21(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H), 6.96(dt, 1H), 7.02(dd, 1H), 7.12(m, 4H); MS(APCI)m/z(rel intensity)403.3(100). 80% yield. 70 CH₂(3-CH₃)Ph mp 80–97° C.; ¹H NMR(CDCl₃): δ2.26(d, 3H), 2.34(s, 3H), 2.57(dd, 1H), 2.69(dd, 1H), 2.87–2.74(m, 2H), 3.03–2.93(m, 3H), 3.96(bd, 1H), 4.41(bd, 1H), 4.93(s, 1H), 6.21(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H), 6.96(dt, 1H), 7.06–7.00(m, 4H), 7.23–7.17(m, 1H); MS(APCI)m/z(rel intensity)403.3(100). 55% yield. 71 CH₂(2-F)Ph mp 84–102° C.; ¹H NMR(CDCl₃): δ2.24(s, 3H), 2.74–2.65(m, 2H), 2.86–2.79(m, 1H), 2.88(dd, 1H), 3.10–2.92(m, 3H), 4.02(t, 2H), 4.96(s, 1H), 6.19(d, 1H), 6.59(dd, 1H), 6.86(dt, 1H), 6.96(dt, 1H), 7.11–6.99(m, 3H), 7.26–7.19(m, 2H); MS (APCI)m/z(rel intensity)407.4(100). 64% yield. 72 CH₂(3-F)Ph mp 87–99° C.; ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.70–2.59(m, 2H), 2.90–2.75(m, 2H), 3.05–2.92(m, 3H), 3.98(d, 1H), 4.09(d, 1H), 4.96(s, 1H), 6.21–6.19(m, 1H), 6.60(dd, 1H), 6.87(dt, 1H), 7.04–6.91(m, 5H), 7.30–7.24(m, 1H); MS(APCI)m/z(rel intensity)407.4(100). 54% yield. 73 CH₂(4-F)Ph mp 86–99° C.; ¹H NMR(CDCl₃): δ2.23(s, 3H), 2.69–2.57(m, 2H), 2.74(dd, 1H), 2.83(dd, 1H), 3.12–2.91(m, 3H), 3.97(d, 1H), 4.05(d, 1H), 4.97(bs, 1H), 6.16(d, 1H), 6.58(dd, 1H), 6.85(dt, 1H), 7.01–6.92(m, 4H), 7.19–7.14(m, 2H); MS (APCI)m/z(rel intensity)407.4(100). 73% yield. 74 CH₂(2-CF₃)Ph mp 103–108° C.; ¹H NMR(CDCl₃): δ2.25(s, 3H), 2.67(dd, 1H), 2.72–2.82(m, 2H), 2.87(dd, 1H), 2.93–3.07(m, 3H), 4.01(m, 2H), 4.93(s, 1H), 6.19(s, 1H), 6.59(d, 1H), 6.86(t, 1H), 6.94–7.01(m, 2H), 7.34(t, 1H), 7.40(d, 1H), 7.49(t, 1H), 7.67(d, 1H); MS(APCI)m/z(rel intensity)457(100). 54% yield. 75 CH₂(2-OCH₃)Ph mp 95–109° C.; ¹H NMR(CDCl₃): δ2.23(s, 3H), 2.66(dd, 1H), 2.71(dd, 1H), 2.90–2.80(m, 2H), 3.09–2.93(m, 3H), 3.83(s, 3H), 4.06–3.98(m, 2H), 4.98(bs, 1H), 6.17(s, 1H), 6.60(dd, 1H), 6.92–6.84(m, 3H), 6.96(dt, 1H), 7.02(dd, 1H), 7.18(dd, 1H), 7.22(dt, 1H); MS(APCI)m/z(rel intensity)419.4(100). 54% yield. 76 CH₂(3-OCH₃)Ph mp 96–109° C.; ¹H NMR(CDCl₃): δ2.24(s, 3H), 2.64–2.91(m, 4H), 3.12–3.01(m, 3H), 3.79(s, 3H), 4.01(bd, 1H), 4.09(bd, 1H), 5.06(bs, 1H), 6.17(s, 1H), 6.60(d, 1H), 6.89–6.75(m, 4H), 6.95(t, 1H), 7.02(d, 1H), 7.21(dt, 1H); MS(APCI)m/z (rel intensity)419.4(100). 25% yield. 77 CH₂(4-OCH₃)Ph mp 85–98° C.: ¹H NMR(CDCl₃): δ2.23(s, 3H), 2.56(dd, 1H), 2.66(dd, 1H), 2.72(dd, 1H), 2.81(dt, 1H), 3.02–2.91(m, 3H), 3.77(s, 3H), 3.98(d, 1H), 4.06(d, 1H), 4.98(bs, 1H), 6.17(s, 1H), 6.58(dd, 1H), 6.87–6.80(m, 3H), 6.94(dt, 1H), 6.99(dd, 1H), 7.15–7.10(m, 2H); MS(APCI)m/z(rel intensity)419.5 (100). 17% yield. 78 CH₂(34,-Di-Cl)Ph mp 108–114° C.; ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.58(dd, 1H), 2.66(dd, 1H), 2.74(dd, 1H), 2.85(ddd, 1H), 2.93–3.03(m, 3H), 3.96(m, 1H), 4.07(m, 1H), 4.97(s, 1H), 6.19(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 6.94–7.03(m, 2H), 7.07(d, 1H), 7.36–7.42(m, 2H; MS(APCI)m/z(rel intensity)457(100), 457(68). 48% yield. 79 CH₂(indol-3-yl) mp 146–158° C.; ¹H NMR(CDCl₃): δ2.16(s, 3H), 2.84–2.68(m, 3H), 3.05–2.88(m, 3H), 3.17–3.07(m, 1H), 3.95(d, 1H), 4.14(bs, 1H), 5.07(bs, 1H), 6.15(bs, 1H), 6.57(d, 1H), 6.84(t, 1H), 6.94(t, 1H), 7.06–7.00(m, 2H), 7.09(t, 1H), 7.17(t, 1H), 7.33(d, 1H), 7.63(d, 1H), 8.26(bs, 1H); MS(APCI)m/z (rel intensity)428.4(100). 55% yield. 80 CH₂(thiophen-2-yl) mp 95–104° C.; ¹H NMR(CDCl₃): δ2.27(s, 3H), 2.68(dd, 1H), 2.84–2.90(m, 2H), 2.94–3.04(m, 4H), 3.98(m, 1H), 4.10(m, 1H), 5.04(bs, 1H), 6.24(s, 1H), 6.59(d, 1H), 6.86(m, 2H), 6.93–6.97(m, 2H), 7.02(d, 1H), 7.17(d, 1H); MS(APCI)m/z (rel intensity)395(100). 10% yield. 81 CH₂(benzo(b)thiophen-3-yl) mp 115–124° C.; ¹H NMR(CDCl₃): δ2.20(s, 3H), 2.73(dd, 1H), 2.82(dd, 1H), 3.05–2.85(m, 4H), 3.22–3.14(m, 1H), 3.95(d, 1H), 4.16(d, 1H), 4.97(bs, 1H), 6.14(d, 1H), 6.57(dd, 1H), 6.85(dt, 1H), 6.95(dt, 1H), 7.01(dd, 1H), 7.22(s, 1H), 7.34(dd, 1H), 7.38(dd, 1H), 7.79(dd, 1H), 7.85(dd, 1H); MS (APCI)m/z(rel intensity)445.4(100). 28% yield. 82 CH₂(3-O-i-Pr—Ph) ¹H NMR(CDCl₃)δ1.33(dd, 6H), 2.26(s, 3H), 2.55–3.01(m, 7H), 3.98(d, 1H), 4.11(d, 1H), 4.55(m, 1H), 4.93(s, 1H), 6.21(s, 1H), 6.59(d, 1H), 6.77(m, 3H), 6.87(t, 1H), 6.98(m, 2H), 7.21(t, 1H); MS(ESI)m/z(rel intensity)447(100). Product isolated as a yellow solid. 83 (R)CH₂Ph mp 84–98° C.: ¹H NMR(CDCl₃)δ2.26(s, 3H), 2.61(dd, 1H), 2.68(dd, 1H), 2.71–2.87(m, 2H), 2.92–3.03(m, 3H), 3.99(d, 1H), 4.09(d, 1H), 4.93(s, 1H), 6.20(s, 1H), 6.59(d, 1H), 6.87(t, 1H), 6.96(t, 1H), 7.03(d, 1H), 7.20–7.33(m, 5H); MS (APCI)m/z(rel intensity)389(100). 83% yield. 84 CH₂(2,4-di-OCH₃)Ph ¹H NMR(CDCl₃)δ2.24(s, 3H), 2.55(dd, 1H), 2.65(m, 1H), 2.75(dd, 1H), 2.84(ddd, 1H), 2.91–3.04(m, 3H), 3.80(s, 6H), 3.99–4.03(m, 2H), 4.95(s, 1H), 6.19(s, 1H), 6.42(d, 1H), 6.46(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.02(d, 1H), 7.06(d, 1H); MS(APCI)m/z(rel intensity)449(100). Product isolated as a a yellow solid. 85 CH₂(4-Cl)Ph mp 91–108° C.; ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.61(dd, 1H), 2.66(dd, 1H), 2.75(dd, 1H), 2.88–2.81(m, 1H), 3.03–2.91(m, 3H), 3.99(bd, 1H), 4.07(bd, 1H), 4.95(bs, 1H), 6.17(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H), 6.97(dt, 1H), 7.01(dd, 1H), 7.19– 7.14(m, 2H), 7.30–7.25(m, 2H); MS(APCI)m/z(rel intensity) 423.4(100). 63% yield. 86 CH₂(2-Cl)Ph ¹H NMR(CDCl₃): δ2.24(s, 3H), 2.65–3.14(m, 7H), 3.99–4.05(m, 2H), 4.96(s, 1H), 6.20(s, 1H), 6.59(d, 1H), 6.87(t, 1H), 6.97(t, 1H), 7.02(d, 1H), 7.18–7.22(m, 2H), 7.27(m, 1H), 7.39(m, 1H); MS(APCI)m/z(rel intensity)423(100), 425(39). 200 mg of product. 87 CH₂(3-Cl)Ph ¹H NMR(CDCl₃): δ2.28(s, 3H), 2.58–3.04(m, 5H), 3.98(m, 1H), 4.08(m, 1H), 4.96(s, 1H), 6.21(s, 1H), 6.61(d, 1H), 6.88(t, 1H), 6.98(t, 1H), 7.03(d, 1H), 7.11(m, 1H), 7.21–7.28(m, 3H); MS(APCI)m/z(rel intensity)423(100), 425(39). 88 CH₂(3,5-Di-F)Ph ¹H NMR(CDCl₃): δ2.27(s, 3H), 2.58–2.70(m, 2H), 2.77(dd, 1H), 2.83–3.06(m, 4H), 3.95(m, 1H), 4.07(m, 1H), 4.99(s, 1H), 6.21(s, 1H), 6.60(d, 1H), 6.69(t, 1H), 6.76–6.83(m, 2H), 6.87(t, 1H), 6.96(t, 1H), 7.01(d, 1H); MS(APCI)m/z(rel intensity)425(100). 10 mg of product. 89 CH₂(3-CF₃)Ph mp 105–117° C.: ¹H NMR(CDCl₃): δ2.24(s, 3H), 2.68–2.73(m, 2H), 2.82–2.89(m, 2H), 2.95–3.10(m, 3H), 3.98(m, 1H), 4.11(m, 1H), 5.00(s, 1H), 6.19(s, 1H), 6.60(d, 1H), 6.88(t, 1H), 6.96(t, 1H), 7.01(d, 1H), 7.42–7.50(m, 4H); MS(APCI) m/z(rel intensity)457(100).

Example 90 2-Methyl-10-(4-methyl-3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

Add aqueous 37% formaldehyde (45 mL, 0.55 mmol) to a solution of 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene (200 mg, 0.5 mmol) in dichloroethane (30 mL). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (159 mg, 0.75 mmol). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry (MgSO₄), filter and concentrate. Purify the residue via chromatography eluting with methylene chloride/methanol (90:10) to provide the title compound as a yellow solid (143 mg, 67%): mp 87–91° C.: ¹H NMR (CDCl₃): δ1.78 (m, 1H), 1.96 (m, 1H), 2.22 (m, 1H), 2.32 (s, 3H), 2.35 (s, 3H), 2.38 (ddd, 1H), 2.58 (ddd, 1H), 2.75 (ddd, 1H), 2.86 (ddd, 1H), 2.94 (dd, 1H), 3.16 (ddd, 1H), 3.90 (m, 1H), 4.05 (m, 1H), 4.94 (s, 1H), 6.30 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.98 (t, 1H), 7.04 (d, 1H), 7.17–7.32 (m, 5H); MS (APCI) m/z (rel intensity) 417 (100).

Example 91 (S)-2-Methyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Dissolve (S)-2-methyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene in ethyl acetate add hydrochloride acid until the title compound precipates as the dihydrochloride salt as a yellow solid: mp 225° C.; mass spectrum (ion spray): m/z=417 (M+1); Analysis for C₂₅H₃₀Cl₂N₄S(0.3 H₂O): calcd: C, 60.67; H, 6.23; N. 11.32; found: C, 60.76; H, 6.17; N, 11.13.

By method similar Example 90, using the appropriate starting materials, the following compounds were prepared and isolated as the free base and as the (S) isomer except where noted:

No: ArAlk Data 92 CH₂Ph mp 94–97° C.; ¹H NMR(CDCl₃): δ2.12(s, 3H), 2.36–2.48(m, 3H), 2.49(s, 3H), 2.79(ddd, 1H), 2.92(ddd, 1H), 3.12–3.23(m, 2H), 3.58(m, 1H), 3.94(m, 1H), 4.90(s, 1H), 5.96(s, 1H), 6.57(d, 1H), 6.82–6.86(m, 1H), 6.91–6.96(m, 1H), 7.14–7.29(m, 5H); MS(APCI)m/z(rel intensity)403(100), 346(80). 93% yield. 93 CH₂(4-O—CH₂CH═CH₂)Ph mp 97–108° C.; ¹H NMR(CDCl₃)δ2.12(s, 3H), 2.39–2.32(m, 2H), 2.43(dd, 1H), 2.48(s, 3H), 2.78(m, 1H), 2.90(dt, 1H), 3.09(d, 1H), 3.21(m, 1H), 3.60(d, 1H), 3.97(d, 1H), 4.49(dt, 2H), 4.94(bs, 1H), 5.30–5.25(m, 1H), 5.43–5.36(m, 1H), 5.96(s, 1H), 6.10–5.98(m, 1H), 6.56(dd, 1H), 6.86–6.78(m, 3H), 6.95–6.91(m, 2H), 7.05(d, 1H); MS(APCI)m/z(rel intensity) 459.4(39), 665.5(100). 71% yield. 94 CH₂(pyridin-2-yl) mp 94–102° C.; ¹H NMR(CDCl₃)δ2.18(s, 3H), 2.44(dd, 1H), 2.49(s, 3H), 2.70(dd, 1H), 2.76(dt, 1H), 2.95–2.84(m, 2H), 3.23(ddd, 1H), 3.30(dd, 1H), 3.58(d, 1H), 3.93(d, 1H), 4.95(bs, 1H), 6.08(s, 1H), 6.57(dd, 1H), 6.84(ddd, 1H), 6.98–6.89(m, 2H), 7.19–7.09(m, 2H), 7.57(dt, 1H), 8.55(m, 1H); MS (APCI)m/z(rel intensity)311.3(100), 404.3(74). 82% yield. 95 (R)CH₂Ph mp 64–82° C.: ¹H NMR(CDCl₃)δ2.12(s, 3H), 2.36–2.48(m, 3H), 2.49(s, 3H), 2.79(ddd, 1H), 2.92(ddd, 1H), 3.12–3.23(m, 2H), 3.58(m, 1H), 3.94(m, 1H), 4.90(s, 1H), 5.96(s, 1H), 6.57(d, 1H), 6.82–6.86(m, 1H), 6.91–6.96(m, 2H), 7.14–7.29(m, 5H); MS(APCI)m/z(rel intensity)403(100), 346(80). 87% yield. 89% yield. 100 CH₂(naphthalen-2-yl) mp 89–102° C.; ¹H NMR(CDCl₃): δ1.70(bs, 3H), 2.43(m, 1H), 2.50(m, 1H), 2.52(s, 3H), 2.59(m, 1H), 2.86(m, 1H), 2.93(m, 1H), 3.22(m, 1H), 3.34(dd, 1H), 3.62(m, 1H), 4.02(m, 1H), 4.86(s, 1H), 5.83(s, 1H), 6.55(d, 1H), 6.80–6.92(m, 3H), 7.30(d, 1H), 7.44(m, 2H), 7.60(s, 1H), 7.73–7.83(m, 3H); MS (APCI)m/z(rel intensity)453(100). 71% yield. 101 CH₂(naphthalen-1-yl) mp 98–116° C.; ¹H NMR(CDCl₃): δ1.87(bs, 3H), 2.47(m, 1H), 2.64(m, 1H), 2.65(s, 3H), 2.80–2.94(m, 2H), 3.00(m, 1H), 3.23(m, 1H), 3.43(m, 1H), 3.77(dd, 1H), 3.97(m, 1H), 4.92(s, 1H), 5.72(bs, 1H), 6.53(d, 1H), 6.80–6.92(m, 3H), 7.28–7.36(m, 2H), 7.45–7.55(m, 2H), 7.71(d, 1H), 7.86(d, 1H), 8.07(d, 1H); MS(APCI)m/z(rel intensity)453(100). 58% yield. 102 CH₂(4-CH₃)Ph mp 81–93° C.; ¹H NMR(CDCl₃): δ2.12(s, 3H), 2.31(s, 3H), 2.45–2.35(m, 3H), 2.49(s, 3H), 2.82–2.72(m, 1H), 2.92(dt, 1H), 3.23–3.09(m, 2H), 3.61(d, 1H), 4.00(bd, 1H), 4.90(s, 1H), 5.96(bs, 1H), 6.58–6.55(m, 1H), 6.85(ddd, 1H), 6.96–6.92(m, 2H), 7.09–7.02(m, 4H); MS(APCI)m/z(rel intensity)417.4 (100). 73% yield 103 CH₂(3-CH₃)Ph mp 67–83° C.; ¹H NMR(CDCl₃): δ2.31(s, 3H), 2.40(s, 3H), 2.47–2.36(m, 3H), 2.49(s, 3H), 2.86–2.76(m, 1H), 2.91(dt, 1H), 3.25–3.06(m, 2H), 3.61(d, 1H), 3.99–3.88(m, 1H)4.89(s, 1H), 5.97(s, 1H), 6.57(d, 1H), 6.88–6.81(m, 1H), 7.02–6.96(m, 5H), 7.19–7.10(m, 1H); MS(APCI)m/z(rel intensity)417.3 (100). 74% yield. 104 CH₂(2-F)Ph mp 69–81° C.; ¹H NMR(CDCl₃): δ2.14(s, 3H), 2.52(s, 3H), 2.53–2.38(m, 3H), 2.95–2.82(m, 2H), 3.26–3.17(m, 2H), 3.58(d, 1H), 3.95(d, 1H), 4.90(s, 1H), 6.03(s, 1H), 6.58–6.54(m, 1H), 6.87–6.82(m, 1H), 7.05–6.90(m, 4H), 7.21–7.14(m, 2H); MS(APCI)m/z(rel intensity)421.3(100). 94% yield. 105 CH₂(3-F)Ph mp 74–88° C.; ¹H NMR(CDCl₃): δ2.16(s, 3H), 2.48(s, 3H), 2.52–2.39(m, 3H), 2.82(dd, 1H), 2.91(dt, 1H), 3.17–3.14(m, 1H), 3.26–3.18(m, 1H), 3.57(d, 1H), 3.95(d, 1H), 4.19(s, 1H), 6.02(s, 1H), 6.58–6.55(m, 1H), 6.98–6.82(m, 6H), 7.26–7.18(m, 1H); MS(APCI)m/z(rel intensity)421.3(100). 81% yield. 106 CH₂(4-F)Ph mp 76–84° C.; ¹H NMR(CDCl₃): δ2.08(s, 3H), 2.43(s, 3H), 2.45–2.23(m, 3H), 2.76–2.65(m, 1H), 2.86(dt, 1H), 3.07(d, 1H), 3.22–3.07(m, 1H), 3.52(bd, 1H), 3.90(bd, 1H), 5.05–4.79(m, 1H), 5.90(s, 1H), 6.50(d, 1H), 6.81–6.75(m, 1H), 6.92–6.83(m, 4H), 7.08–7.02(m, 2H); MS(APCI)m/z(rel intensity)421.4 (100). 81% yield. 107 CH₂(3-CF₃)Ph mp 88–105° C.; ¹H NMR(CDCl₃): δ2.11(s, 3H), 2.51(s, 3H), 2.60–2.38(m, 3H), 2.96–2.78(m, 2H), 3.30–3.16(m, 2H), 3.59(bd, 1H), 3.92(bd, 1H), 4.92(s, 1H), 5.99(s, 1H), 6.57(d, 1H), 6.96–6.82(m, 3H), 7.50–7.36(m, 4H); MS(APCI)m/z(rel intensity)471.3(100). 57% yield. 108 CH₂(2-CF₃)Ph ¹H NMR(CDCl₃): δ2.14(s, 3H), 2.46(m, 2H), 2.50(s, 3H), 2.62(m, 1H), 2.70(m, 1H), 2.90–2.97(m, 2H), 3.24(m, 1H), 3.42(dd, 1H), 3.46(dd, 1H), 4.93(s, 1H), 6.04(s, 1H), 6.57(d, 1H), 6.86(t, 1H), 6.90–6.97(m, 2H), 7.26–7.40(m, 2H), 7.43(t, 1H), 7.64(d, 1H); MS(APCI)m/z(rel intensity)471(100). 58% yield. 109 CH₂(2-OCH₃)Ph mp 81–93° C.; ¹H NMR(CDCl₃): δ2.12(s, 3H), 2.49(m, 3H), 2.51(s, 3H), 2.90–2.83(m, 1H), 2.92(dt, 1H), 3.25–3.16(m, 2H), 3.57(d, 1H), 3.79(s, 3H), 3.96(bd, 1H), 4.89(s, 1H), 5.98(bs, 1H); 6.56(dd, 1H), 6.87–6.81(m, 3H), 6.95–6.91(m, 2H), 7.08(d, 1H), 7.19(dt, 1H); MS(APCI)m/z(rel intensity)433.4 (100). 73% yield. 110 CH₂(3-OCH₃)Ph mp 70–82° C.; ¹H NMR(CDCl₃): δ2.13(s, 3H), 2.48–2.37(m, 3H), 2.49(s, 3H), 2.79(dd, 1H), 2.91(dt, 1H), 3.23–3.11(m, 2H), 3.62(d, 1H), 3.77(s, 3H), 3.98(d, 1H), 4.90(bs, 1H), 5.99(s, 1H), 6.57(d, 1H), 6.77–6.69(m, 3H), 6.85(ddd, 1H), 6.95– 6.92(m, 2H), 7.18(t, 1H); MS(APCI)m/z(rel intensity)433.3 (100). 68% yield. 111 CH₂(4-OCH₃)Ph mp 74–88° C.; ¹H NMR(CDCl₃): δ2.10(s, 3H), 2.44–2.29(m, 3H), 2.46(s, 3H), 2.74(dd, 1H), 2.89(dt, 1H), 3.08(d, 1H), 3.16(ddd, 1H), 3.58(d, 1H), 3.76(s, 3H), 3.97(d, 1H), 4.90(bs, 1H), 5.94(s, 1H), 6.54(d, 1H), 6.84–6.76(m, 3H), 6.93–6.89(m, 2H), 7.06–7.02(m, 2H); MS(APCI)m/z(rel intensity)433.3(50), 242.5(100). 74% yield. 112 CH₂(3,4-di-Cl)Ph mp 87–94° C.; ¹H NMR(CDCl₃): δ2.17(s, 3H), 2.38–2.50(m, 3H), 2.47(s, 3H), 2.82–2.93(m, 2H), 3.08(ddd, 1H), 3.24(ddd, 1H), 3.57(d, 1H), 3.91(m, 1H), 4.92(s, 1H), 6.01(s, 1H), 6.57(d, 1H), 6.86(m, 1H), 6.92–6.97(m, 2H), 7.01(dd, 1H), 7.27(d, 1H), 7.32(d, 1H); MS(APCI)m/z(rel intensity)471(100), 473 (62). 54% yield. 113 CH₂(indol-3-yl) mp 138–156° C.; ¹H NMR(CDCl₃): δ1.90(s, 3H), 2.43(dt, 1H), 2.55(s, 3H), 2.67–2.51(m, 2H), 2.90–2.78(m, 1H), 2.94(bd, 1H), 3.31–3.17(m, 2H), 3.74(bd, 1H), 3.98(bd, 1H), 4.94(bs, 1H), 5.87(s, 1H), 6.51(d, 1H), 6.83–6.77(m, 1H), 6.93–6.88(m, 2H), 6.96(s, 1H), 7.10(dt, 1H), 7.16(dt, 1H), 7.31(d, 1H), 7.59(d, 1H), 8.18(bs, 1H); MS(APCI)m/z(rel intensity)442.4 (100). 63% yield. 114 CH₂(thiophen-2-yl) mp 85–87° C.; ¹H NMR(CDCl₃): δ2.20(s, 3H), 2.39–2.48(m, 2H), 2.47(s, 3H), 2.79–2.85(m, 2H), 2.90(ddd, 1H), 3.18(ddd, 1H), 3.27(dd, 1H), 3.73(m, 1H), 3.97(m, 1H), 4.91(s, 1H), 6.11(s, 1H), 6.57(d, 1H), 6.79–7.00(m, 5H), 7.13(d, 1H); MS (APCI)m/z(rel intensity)409(100). 53% yield. 115 CH₂(benzo(b)thiophen-3-yl) mp 84–97° C.; ¹ H NMR(CDCl₃): δ1.99(s, 3H), 2.46(dt, 1H), 2.56(s, 3H), 2.70–2.62(m, 1H), 2.76(dd, 1H), 2.97–2.85(m, 2H), 3.26(t, 1H), 3.34(dd, 1H), 3.67(d, 1H), 3.94(d, 1H), 4.88(bs, 1H), 5.88(s, 1H), 6.53(d, 1H), 6.85–6.79(m, 1H), 6.94–6.88(m, 2H), 7.16(s, 1H), 7.33(dd, 1H), 7.37(dd, 1H), 7.74(d, 1H), 7.83(d, 1H); MS(APCI)m/z(rel intensity)459.3(100). 82% yield. 118 CH₂(2-Cl)Ph ¹H NMR(CDCl₃): δ2.14(s, 3H), 2.34–2.67(m, 3H), 2.54(s, 3H), 2.91–2.96(m, 2H), 3.22(ddd, 1H), 3.38(m, 1H), 3.52(m, 1H), 3.93(m, 1H), 4.92(s, 1H), 6.04(s, 1H), 6.56(d, 1H), 6.86(t, 1H), 6.92–6.97(m, 2H), 7.12–7.19(m, 3H), 7.36(m, 1H); MS (APCI)m/z(rel intensity)437(100), 439(39). 119 CH₂(3-Cl)Ph ¹H NMR(CDCl₃): δ2.16(s, 3H), 2.42–2.48(m, 3H), 2.49(s, 3H), 2.83(m, 1H), 2.90(m, 1H), 3.13(dd, 1H), 3.24(ddd, 1H), 3.57(ddd, 1H), 3.93(m, 1H), 4.92(s, 1H), 6.01(s, 1H), 6.57(d, 1H), 6.85(m, 1H), 6.93–6.96(m, 2H), 7.05(m, 1H), 7.16–7.20(m, 3H); MS(APCI)m/z(rel intensity)437(100), 439(44). 120 CH₂(4-Cl)Ph mp 64–77° C.: ¹H NMR(CDCl₃): δ2.16(s, 3H), 2.48(s, 3H), 2.51–2.33(m, 3H), 2.78(dd, 1H), 2.90(dt, (1H), 3.19(ddd, 1H), 3.57(d, 1H), 3.97(bd(1H), 4.91(bs, 1H), 5.96(d, 1H), 6.57(dd, 1H), 6.85(ddd, 1H), 6.96–6.91(m, 2H), 7.12–7.07(m, 2H), 7.27– 7.21(m, 2H); MS(APCI)m/z(rel intensity)437(100), 439(44). 121 CH₂(4-OPh)Ph mp 94–101° C.; ¹H NMR(CDCl₃)δ2.17(s, 3H), 2.48–2.38(m, 2H), 2.49(s, 3H), 2.81(m, 1H), 2.92(dt, 1H), 3.14(d, 1H), 3.23(t, 1H), 3.61(d, 1H), 3.94(d, 1H), 5.10–4.91(m, 1H), 6.08(bs, 1H), 6.56(d, 1H), 6.83(ddd, 1H), 6.98–6.88(m, 6H), 7.14–7.05(m, 4H), 7.35–7.29(m, 2H); MS(APCI)m/z(rel intensity)495.7 (100). 80% yield. 122 CH₂(3-OPh)Ph mp. 89–93° C.: ¹H NMR(CDCl₃)δ2.14(s, 3H), 2.50–2.40(m, 3H), 2.47(s, 3H), 2.80(bs, 1H), 2.93(d, 1H), 3.14(d, 1H), 3.28(bs, 1H), 3.60(d, 1H), 3.96(d, 1H), 4.90(s, 1H), 5.97(s, 1H), 6.56(dd, 1H), 6.90–6.82(m, 3H), 7.01–6.91(m, 5H), 7.09(ddd, 1H), 7.24(t, 1H), 7.36–7.30(m, 2H); MS(APCI)m/z(rel intensity)495.4(100). 94% yield. 123 CH₂(3-O-i-Pr)Ph ¹H NMR(CDCl₃)δ1.29(dd, 6H), 2.14(s, 3H), 2.40(m, 3H), 2.48(s, 3H), 2.80(m, 1H), 2.90(dt, 1H), 3.15(m, 2H), 3.61(d, 1H), 3.98(m, 1H), 4.51(m, 1H), 4.89(s, 1H), 5.98(s, 1H), 6.57(d, 1H), 6.72(m, 3H), 6.84(m, 1H), 6.93(d, 12H), 7.16(t, 1H); MS(ESI)m/z(rel intensity)461(100). Product isolated as a yellow solid 124 CH₂(2,4-di-OCH₃)Ph ¹H NMR(CDCl₃)δ2.12(s, 3H), 2.31–2.47(m, 3H), 2.49(s, 3H), 2.82(m, 1H), 2.91(ddd, 1H), 3.11(dd, 1H), 3.19(ddd, 1H), 3.58(m, 1H), 3.75(s, 3H), 3.78(s, 3H), 3.97(m, 1H), 4.94(s, 1H), 5.97(s, 1H), 6.36–6.45(m, 2H), 6.56(d, 1H), 6.83(m, 1H), 6.91–6.97(m, 3H); MS(APCI)m/z(rel intensity)463(100). Product isolated as a yellow solid.

Example 125 2-Methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-ylamine

Dissolve 2-methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-ylamine hydrochloride (6 g, 22.6 mmoles) in a 5:1 mixture of dichloromethane and commercial 7N ammonia-methanol, wash with half a volume of 5N aqueous sodium hydroxide. Separate the organic layer and extract the aqueous layer twice with dichloromethane. Combine all organic extracts, dry over magnesium sulfate, filter and concentrate in vacuo to yield the title free base as an orange solid: ¹H NMR (DMSO-d₆): δ8.10–7.80 (br, 1H), 7.30–6.90 (br, 2H), 6.80–6.65 (m, 3H), 6.59 (br dd, 1H, J=7.6, 1.6 Hz), 6.52 (br s, 1H), 2.22 (br s, 3H).

Example 126 2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylamine

Slurry 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylamine hydrochloride (5.2 g, 19.5 mmol) in water and add 1N sodium hydroxide (19.5 mL, 19.5 mmol). Add methanol to facilitate stirring and extract with methylene chloride. Purify the methylene chloride extracts by silica gel chromatography using 7N ammonia in methanol-methylene chloride (5%) as the eluent to give (4.13 g, 92%) of the title compound.

Example 127 and Example 127a (S)-1,4-Dibenzyl-2-vinylpiperazine (R)-1,4-Dibenzyl-2-vinylpiperazine

Add anhydrous tetrahydrofuran (4.5 L) to a 10 L flange-neck flask equipped with an air stirrer rod and paddle, thermometer, and nitrogen inlet and outlet tubes. Purge with dry nitrogen gas (inlet tube had a sintered end for maximum gas dispersal) the body of the liquid for 1 h, add tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (36.0 g, 34.8 mmol). Add isopropyl phosphite (67.8 mL, 0.275 mol) in one lot to the mixture still under nitrogen and stir. After 5 minutes, the color lightens from purple to amber. Add dibenzylethylenediamine (322.0 g, 1.34 mol) in one lot, followed by the dropwise addition of cis-1,4-diacetoxy-2-butene (214 mL, 1.34 mol) over 15 minutes stir under nitrogen for 18 hours. Remove the solvent in vacuo at 40° C. and dissolve the residual oil in diethyl ether (2.5 L) and extract with 1N aq. sodium hydroxide (2×2 L). Wash the bulked aqueous extracts with diethyl ether (2×) and basify to pH 14 using 5N aq. sodium hydroxide and extract with diethyl ether (3×). Dry the bulked ethereal extracts over magnesium sulphate, filter and evaporate to dryness in vacuo at 40° C. Purification by chromatography on silica (117 kg) using 1% methanol/ether (can also use dichloromethane) gives a pale yellow oil (377.35 g, 96%) 1H NMR and Mass Spec are consistent with product.

Dissolve the mixture of isomers in ethyl acetate (3670 mL) and add portionwise to a hot solution of (S)-(+)-mandelic acid (385 g, 2 eq.) in ethyl acetate (3850 mL), starting at 72° C. Chill the mixture to 0° C. and seed with crystals (which were previously obtained from an earlier resolution). Place the mixture in the freezer (−20° C.) overnight. Scrape the crystalline solid away from the sides of the flask and allow the mixture to warm to 0° C. Isolate the solid dry. Further dry the material in vacuo at room temperature. Yield=252.6 g, white, crystalline solid of the S-mandelic acid salt of the (R)-1,4-dibenzyl-2-vinylpiperazine.

Evaporate the filtrate to dryness in vacuo at 40° C. to leave an amber oil. Dissolve the filtrate in dichloromethane (2 L) and wash the solution with 1N aq. sodium hydroxide (2 L+1 L), brine (1 L) and dry over magnesium sulphate. Filter and evaporate to dryness in vacuo at 45° C. to yield the recovered free base. Further dry by vacuum. Extract the aqueous liquors with dichloromethane to further recover any remaining free base (207.6 g). Chiral HPLC showed the material to consist of a 85:15 ratio of isomers in favour of the required isomer.

Add (R)-(−)-mandelic acid (216 g, 1.42 mol) and ethyl acetate (2.5 L) to a 10 liter flange-neck flask equipped with an air stirrer rod and paddle, thermometer and water condenser and warm the suspension to 60° C. Add a solution of free base (207.6 g, 0.71 mol) in ethyl acetate (500 mL) and allow to cool down to room temperature and place in the freezer overnight (at 35° C. solid starts to precipitate). Isolate the crystalline solid by filtration and pull dry. Further dry in vacuo at room temperature(290.34 g).

Recrystallize from hot ethyl acetate (2.3 L) at 70° C. Allow this solution to cool down to room temperature overnight after seeding. Filtration and drying in vacuo at room temperature gives the R-mandelic acid salt of the (S)-1,4dibenzyl-2-vinylpiperazine from which the free base may be prepared (225.44 g). Chiral HPLC showed: 98.74%+1.26%: ¹H NMR, OMSO d₆): δ7.20–7.35 (m, 10H); 5.75–5.90 (m, 1H); 5.15–5.30 (q, 2H); 3.85–3.95 (d, 1H); 3.40–3.45 (s, 2H); 3.00–3.10 (d, 1H); 2.80–2.90 (t, 1H); 2.55–2.60 (d, 3H); 1.95–2.10 (m, 311).

Example 128 (S)-1,4-Dibenzyl-2-(2-pyridin-2-yl-ethyl)-piperazine

Combine 9-borabicyclo[3.3.1]nonane (62.6 mL, 31.3 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine. (2.29 g, 7.83 mmol) and stir at ambient temperature. After 18 hours, add triphenylphosphine (657 mg, 2.50 mmol), tetrakis(triphenylphosphine) palladium(0) (362 mg, 0.31 mmol), and 2-bromopyridine (1.12 mL, 11.7 mmol). Add 3M NaOH (6.4 mL, 19.3 mmol) slowly, and gas evolution will occur. Heat at reflux. After 24 hours, cool to ambient temperature, add 5N HCl (50 mL), and stir 1 hour. Dilute with 0.2 N HCl, extract with diethyl ether, and discard the diethyl ether extracts. Add 5N NaOH to the acidic aqueous solution until pH is 12–14. Extract with diethyl ether. Wash the diethyl ether extracts with water and brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0.5%–3%) as the eluent to give the title compound (2.3 g, 79%): mp 83–86° C.; mass spectrum (ion spray): m/z=372 (M+1). Analysis calculated for C₂₅H₂₉N₃: C, 80.82; H, 7.87; N, 11.31. Found: C, 80.56; H, 7.60; N, 11.30.

Example 129 (S)-1,4-Dibenzyl-2-(2-pridin-4-yl-ethyl)-piperazine

Prepared by the method in Example 128, using 9-borabicyclo[3.3.1]nonane (71.4 mL, 35.7 mmol, 0.5 M in THF), (S)-1,4-dibenzyl-2-vinyl-piperazine (2.61 g, 8.92 mmol), triphenylphosphine (749 mg, 2.86 mmol), tetrakis(triphenylphosphine)palladium(0) (413 mg, 0.36 mmol), 4-bromopyridine hydrochloride (2.60 g, 13.4 mmol) and 3M NaOH (10.4 mL, 31.2 mmol) to give the title compound (1.87 g, 56%): mp 96–98° C.; mass spectrum (ion spray): m/z=372 (M+1). Analysis calculated for C₂₅H₂₉N₃: C, 80.82; H, 7.87; N, 11.31. Found: C, 80.80; H, 7.99; N, 11.18.

Example 130 (S)-2-(2-Pyridin-2-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-pyridin-2-yl-ethyl)-piperazine (2.86 g, 7.69 mmol) in ethanol (50 mL). Add ammonium formate (2.43 g, 38.5 mmol) and palladium (430 mg, 5 wt. % on carbon) and heat to reflux. After 6 hours 40 minutes, filter the palladium on carbon and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (5%–15%) as the eluent to give the title compound (1.1 g, 75%): mp 83–87° C.; mass spectrum (ion spray): m/z=192 (M+1). Analysis calculated for C₁₁H₁₇N₃: C, 69.07; H, 8.96; N, 21.97. Found: C, 68.84; H, 8.85; N, 21.65.

Example 131 (S)-2-(2-Pyridin-4-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-pyridinyl-ethyl)-piperazine (2.14 g, 5.76 mmol) in ethanol (40 mL). Add ammonium formate (2.18 g, 34.6 mmol) and palladium (430 mg, 5 wt. % on carbon) and heat to reflux. After 6 hours 30 minutes, filter the palladium on carbon and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (5%–15%) as the eluent to give 945 mg (86%) of the title compound: mp 113–116° C.; mass spectrum (ion spray): m/z=192 (M+1). Analysis calculated for C₁₁H₁₇N₃: C, 69.07; H, 8.96; N, 21.97. Found: C, 69.08; H, 8.77; N, 21.81.

Example 132 (S)-2-Methyl-10-(3-(2-pyridin-2-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene trihydrochloride

Combine (S)-2-(2-pyridin-2-yl-ethyl)-piperazine (470 mg, 2.46 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (282 mg, 1.23 mmol), toluene (8 mL), and DMSO (2 mL). Heat at 110° C. After 41 hours, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 270 mg. Purify again by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2%–5%) as the eluent to give the free base. Crystallize as the trihydrochloride salt from ethyl acetate and ethanol to give the title compound (20 g, 40%): mp 220–224° C. dec.; mass spectrum (ion spray): m/z=404 (M+1). Analysis calculated for C₂₃H₂₅N₅S.2.7HCl: C, 55.03; H, 5.56; N, 13.95. Found: C, 55.22; H, 5.59; N, 13.81.

Example 133 (S)-2-Methyl-10-(3-(2-pyridin-4-yl-ethyl)-piperazin-1-yl)-4H-3-thia-49-diaza-benzo[f]azulene trihydrochloride

Combine (S)-2-(2-pyridin-4-yl-ethyl)-piperazine (889 mg, 4.65 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (533 mg, 2.32 mmol), toluene (12 mL), and DMSO (3 mL). Heat at 110° C. After 72 hours, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2%–4%) as the eluent to give the free base. Crystallize as the trihydrochloride salt from ethyl acetate and ethanol to give the title compound (486 mg, 52%): mp 234–239° C. dec.; mass spectrum (ion spray): m/z=404 (M+1). Analysis calculated for C₂₃H₂₅N₅S.3HCl: C, 53.86; H, 5.50; N, 13.65. Found: C, 53.71; H, 5.79; N, 13.37.

Example 134 (S)-1,4-Dibenzyl-2-(2-(4-fluoro-phenyl-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 6 hours 30 minutes, add 1-fluoro-4-iodo-benzene (2.3 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 ml) and stir at 60° C. After 22 hours, add ethanolamine (10.0 mL) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 2N ammonia in methanol to give the title compound: mp 79–82° C.; mass spectrum (ion spray): m/z=389.4 (M+1).

Example 135 (S)-1,4-Dibenzyl-2-(2-(3-fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add 1-fluoro-3-iodo-benzene (2.3 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 mL) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 2N ammonia in methanol to give the title compound: mp 69–71° C.; mass spectrum (ion spray): m/z=389.4 (M+1).

Example 136 (S)-1,4-Dibenyl-2-(2-(2-fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add 1-fluoro-2-iodo-benzene (2.3 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 mL) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 2N ammonia in methanol to give the title compound: mp 62–66° C.; mass spectrum (ion spray): m/z=389.4 (M+1).

Example 137 (S)-2-(2-(4-Fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(4-fluoro-phenyl)-ethyl)-piperazine (1.94 g, 4.99 mmol), ammonium formate (1.57 g, 24.95 mmol), 5% Pd/C (241.1 mg), and ethanol (50 mL) and stir and heat the mixture at reflux. After 4 hours 30 minutes, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and dissolve it in 1N NaOH. Extract with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give the title compound as a white solid: mp 112–114° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis for C₁₂H₁₇FN₂: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 68.97; H, 8.14; N, 13.21.

Example 138 (S)-2-(2-(3-Fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(3-fluoro-phenyl)-ethyl)-piperazine (1.96 g, 5.04 mmol), ammonium formate (1.59 g, 25.18 mmol), 5% Pd/C (243.3 mg), and ethanol (50 mL). Stir and heat the mixture at reflux. After 4 hours 30 minutes, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give the title compound as a white solid: mp 95–99° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis for C₁₂H₁₇FN₂: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 69.13; H, 8.40; N, 13.28.

Example 139 (S)-2-(2-(2-Fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(2-fluoro-phenyl)-ethyl)-piperazine (1.06 g, 2.73 mmol), ammonium formate (861.0 mg, 13.66 mmol), 5% Pd/C (132.0 mg), and ethanol (50 mL). Stir and heat the mixture at reflux. After 4 hours 30 minutes, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give (443.8 mg, 78%) of the title compound as a white solid: mp 94–99° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis for C₁₂H₁₇FN₂: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 69.20; H, 8.26; N, 13.57.

Example 140 (S)-2-Phenethyl-piperazine

Combine (S)-1,4-dibenzyl-2-phenethyl-piperazine (5.15 g, 13.90 mmol), ammonium formate (4.38 g, 69.49 mmol), 5% Pd/C (672.5 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify by silica gel chromatography using dichloromethane/7N ammonia in methanol (90:10) to give the title compound as a white solid: mp 116–119° C.; mass spectrum (ion spray): m/z=191.2 (M+1); Analysis for C₁₂H₁₈N₂: calcd: C, 75.74; H, 9.53; N, 14.72; found: C, 75.90; H, 9.57; N, 14.59.

Example 141 (S)-1,4-Dibenyl-2-(2-(4-methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 6 hours and 30 minutes, add 1-iodo-4-methoxy-benzene (2.4 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 ml) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 7N ammonia in methanol to give the title compound: mp 88–91° C.; mass spectrum (ion spray): m/z=401.4 (M+1).

Example 142 (S)-1,4-Dibenzyl-2-(2-(3-methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and 9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stir at ambient temperature. After 6 hours and 30 minutes, add 1-iodo-3-methoxy-benzene (2.4 g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0 ml) and dilute the mixture with water. Extract with ethyl acetate and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellow oil in acetic acid/methanol (1:9) and apply to an SCX column. Wash the column with methanol followed by 7N ammonia in methanol to give the title compound: mp 73–75° C.; mass spectrum (ion spray): m/z=401.4 (M+1).

Example 143 1,4-Dibenzyl-2-styryl-piperazine

Combine 1,4-dibenzyl-2-vinyl-piperazine (200.0 mg, 0.68 mmol), styrene (142.5 mg, 1.37 mmol), bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (168.8 mg, 0.21 mmol), and dichloromethane (8 mL) and stir at reflux. After 24 hours, the reaction mixture was filtered and reduced to residue. The title compound was observed by LC/MS: mass spectrum (ion spray): m/z=369.1 (M+1); R_(f)=0.49 (hexanes/ethyl acetate (40:60)).

Example 144 1,4-Dibenzyl-2-styryl-piperazine

Combine tri-o-tolylphosphine (1.05 g, 3.46 mmol), palladium acetate (175 mg, 0.78 mmol), triethylamine (3.26 mL, 23.4 mmol), iodobenzene (2.74 mL, 24.5 mmol), 1,4-dibenzyl-2-vinyl-piperazine (3.26 g, 11.1 mmol) and acetonitrile (50 mL) in a sealable vessel and purge with nitrogen. Seal the vessel and heat at 110° C. After 20 hours 45 minutes, cool to ambient temperature and dilute with ethyl acetate. Filter and discard the solids. Concentrate the filtrate and purify by silica gel chromatography using ethyl acetate-hexanes (0–100%) as the eluent to give the title compound: mass spectrum (ion spray): m/z=369 (M+1); ¹H NMR (DMSO-d₆): δ7.41 (d, 2H), 7.18–7.34 (m, 13H), 6.64 (d, 1H), 6.27 (dd, 1H), 3.94 (d, 1H), 3.46 (dd, 2H), 3.10 (d, 1H), 3.02 (dt, 1H), 2.56–2.70 (m, 3H), 2.05–2.19 (m, 3H).

Example 145 1,4-Bis-(toluene-4-sulfonyl)-2-vinyl-piperazine

Combine tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (503 mg, 0.49 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (606 mg, 0.97 mmol) and tetrahydrofuran (100 mL) and stir at ambient temperature. After 1 hour 30 minutes, add 1,4-bis-(toluene-4-sulfonyl)-ethane (7.17 g, 19.5 mmol), cis-2-butene-1,4-diol diacetate (3.10 mL, 19.5 mmol) and tetrahydrofuran (100 mL) and heat at 40° C. After 18 hours, cool to ambient temperature and concentrate under vacuum. Purify by silica gel chromatography using ethyl acetate-hexanes (20–60%) as the eluent. Recrystallize from ethyl acetate-hexanes to give the title compound: mp 177–178° C.; mass spectrum (ion spray): m/z=421 (M+1). Analysis calculated for C₂₀H₂₄N₂O₄S₂: C, 57.12; H, 5.75; N, 6.66. Found: C, 56.83; H, 5.26; N, 6.62.

Example 146 2-Styryl-1,4-bis-(toluene-4-sulfonyl)-piperazine

Combine tri-o-tolylphosphine (72 mg, 0.24 mmol), palladium acetate (12 mg, 0.05 mmol), triethylamine (0.22 mL, 1.6 mmol), iodobenzene (0.20 mL, 1.83 mmol), 1,4-bis-(toluene-4-sulfonyl)-2-vinyl-piperazine (320 mg, 0.76 mmol) and acetonitrile (8 mL) in a sealable vessel and purge with nitrogen. Seal the vessel and heat at 110° C. After 21 hours 45 minutes, cool to ambient temperature and dilute with ethyl acetate. Filter and discard the solids. Concentrate the filtrate and purify by silica gel chromatography using ethyl acetate-hexanes (0–30%) as the eluent to give a 8:1 ratio of the title compound to 1,4-bis-(toluene-4-sulfonyl)-2-vinyl-piperazine: mass spectrum (ion spray): m/z=497 (M+1); ¹H NMR(DMSO-d₆): δ7.59 (d, 2H), 7.53 (d, 2H), 7.42 (d, 2H), 7.19–7.36 (m, 7H), 6.48 (d, 1H), 6.08 (dd, 1H), 4.62 (m, 1H), 3.70 (br d, 1H), 3.52 (m, 2H), 3.29 (dd, 1H), 2.41 (s, 3H), 2.29–2.32 (m, 1H), 2.26 (s, 3H), 2.12 (dd, 1H).

Example 147 2-Phenethyl-piperazine

Combine 1,4-dibenzyl-2-styryl-piperazine (289 mg, 0.78 mmol), palladium hydroxide (36 mg, 20 wt. % on carbon), and ethanol (100 mL) in a hydrogenation vessel. Shake and heat at 60° C. under a hydrogen atmosphere (60 psi). After 24 hours, cool to ambient temperature and filter the palladium hydroxide. Concentrate the filtrate and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (20%) as the eluent to give the title compound: mass spectrum (ion spray): m/z=191 (M+1); ¹H NMR (DMSO-d₆): δ7.11–7.31 (m, 5H), 2.82–2.39 (m, 8H), 2.18 (dd, 1H), 1.48 (dd, 2H).

Example 148 (S)-1,4-Dibenzyl-2-(2-pyridin-3-yl-ethyl)-piperazine

Prepared by the method in Example 128, using 9-borabicyclo[3.3.1]nonane (68.4 mL, 34.2 mmol, 0.5 M in THF), (S)-1,4-dibenzyl-2-vinyl-piperazine (2.5 g, 8.55 mmol), triphenylphosphine (718 mg, 2.74 mmol), tetrakis(triphenylphosphine) palladium(0)(395 mg, 0.34 mmol), 3-iodopyridine (2.63 g, 12.8 mmol) and 3M NaOH (7.0 mL, 21.0 mmol) to give title compound (1.28 g, 40%): mp 94–95.5° C.; mass spectrum (ion spray): m/z=372 (M+1). Analysis calculated for C₂₅H₂₉N₃: C, 80.82; H, 7.87; N, 11.31. Found: C, 80.54; H, 7.76; N, 11.32.

Example 149 (S)-2-(2-Pyridin-3-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-pyridin-3-yl-ethyl)-piperazine (1.6 g, 4.31 mmol) in ethanol (30 mL). Add ammonium formate (1.63 g, 25.8 mmol) and palladium (240 mg, 5 wt. % on carbon) and heat to reflux. After 3 hours 30 minutes, add additional ammonium formate (1.63 g, 25.8 mmol). After 3 hours, filter the palladium on carbon and concentrate the filtrate. Slurry the residue in water and methylene chloride, basify with 5N NaOH, and extract with methylene chloride and chloroform-isopropanol (3:1 mixture). Dry the extracts over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%–15%) as the eluent to give (261 mg, 32%) of the title compound: mp 104–110° C.; mass spectrum (ion spray): m/z=192 (M+1). ¹H NMR (DMSO-d₆, D₂O): δ8.42 (d, 1H), 8.38 (dd, 1H), 7.63 (dt, 1H), 7.31 (dd, 1H), 2.38–2.83 (m, 8H), 2.18 (dd, 1H), 1.50 (dd, 2H).

Example 150 Carbonic acid 4-methoxycarbonyloxy-but-2-enyl ester methyl ester

Combine methyl chloroformate (7.04 g, 80.0 mmol) in THF (70 mL) and add dropwise to a ice-water cold solution of 2-buten-1,4-diol (majority Z form) (19.7 g, 208 mmol) and pyridine (16.5 g, 208 mmol) in THF (150 mL). Warm the mixture to room temperature and stir for 20 hours. Remove the pyridine salt by filtration and concentrate the filtrate to a residue. Dissolve the residue with CH₂Cl₂ and wash sequentially with 1 N HCl and brine. Dry the organic layer over Na₂SO₄ and concentrate the solvent in vacuo to give a residue. Purification by chromatography using hexanes: EtOAc=12:1 as the eluents give the title compound: ¹H NMR (CDCl₃): δ5.82–5.79 (m, 2H), 4.75 (d, J=4.8 Hz, 4H), 3.79 (s, 6H).

Example 151 1,2-Bis(p-tolysulfonylamino)ethane

Using ethylenediamine (72 g, 1.2 mol), p-toluenesulfonyl chloride (500 g, 2.6 mol), sodium hydroxide (330 g, 8.25 mol), 6 N HCl (400 mL) and following the procedure described in Caribb. J. Sci., 14, 77 (1974), gives the title compound as white solid.

Example 152 1,2-Bis(p-methoxybenzenesulfonylamino)ethane

Combine ethylenediamine (0.9 g, 15 mmol) in CH₂Cl₂ (50 mL) and mix with triethylamine (3.03 g, 30 mmol). Cool the mixture on a ice-water bath and add dropwise 4-methoxybenzenesulfonyl chloride (6.2 g, 30 mmol) in CH₂Cl₂ (50 mL). Warm the reaction to room temperature and stir overnight. Wash the reaction with 1N HCl (100 mL), sat. NaHCO₃, brine, dry over Na₂SO₄, and concentrate the crude product in vacuo. Purification by flash chromatography (CH₂Cl₂/EtOAc=5:1) gives the title compound: Mass spectrum (electrospray): (m/z)=401.1 (M+1); ¹H NMR (CDCl₃): δ7.77–7.74 (m, 4H), 6.99–6.96 (m, 4H), 4.95 (br, 2H), 3.87 (s, 6H), 3.06–3.04 (m, 4H).

Example 153 1,2-Bis(o-nitrobenzenesulfonylamino)ethane

By a method similar to Example 152, using ethylenediamine (0.9 g, 15 mmol), triethylamine (3.03 g, 30 mmol), 2-nitrophenyl sulfonyl chloride 6.63 g, 30 mmol) gives the title compound: Mass spectrum (electrospray): (m/z)=431.1 (M+1); ¹H NMR (DMSO-d₆): δ8.19 (br, 2H), 8.017.86 (m, 8H), 3.00–2.99 (m, 4H).

Example 154 1.2-Bis(2,4,6-trimethylbenzenesulfonylamino)ethane

By a method similar to Example 152, using ethylenediamine (0.9 g, 15 mmol), triethylamine (3.03 g, 30 mmol), 2-mesitylenesulfonyl chloride (6.56 g, 30 mmol) gives the title compound. Mass spectrum (electrospray): (m/z)=425.2 (M+1); ¹H NMR (DMSO-d₆): δ7.28 (br, 2H), 7.01 (s, 4H), 2.69–2.68 (m, 4H), 2.47 (s, 12H), 2.28 (s, 6H).

Example 155 1,4-Bis(toluene-4-sulfonyl)-2-vinyl-piperazine

Combine tris(dibenzylideneacetone)dipalladium chloroform ((dba)₃Pd₂ CHCl₃)(13 mg, “pd” 0.025 mmol) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 15.6 mg, 0.025 mmol) in THF (2.5 mL) under N₂ and stir at room temperature. After 1 hour, add 1,2-bis(p-toylsulfonylamine) ethane (184 mg, 0.5 mmol),(Z)-1,4-bis(methoxycarbonyloxy)but-2-ene (102 mg, 0.5 mmol), and THF (2.5 mL) and heat to 40° C. After 24 hours, cool to room temperature and concentrate the reaction under reduced pressure to give a brown solid. Wash the solid with ether (3×5 mL), dissolve in CH₂Cl₂, pass through a plug of silica gel to remove insoluble material and concentrate the filtrate. Purification by Chiral HPLC: Chiralpak AD(0.46×25 cm), IPA:Heptane 40:60, 1 mL/min, Retention Time: 14.53, 18.01 min or by flash chromatography on silica gel, gradient: CH₂Cl₂ to 2.5% EtOAc in CH₂Cl₂ to give the title compound: ¹H NMR (CDCl₃): δ7.60–7.56 (m, 4H), 7.35–7.32 (m, 2H), 7.26–7.23 (m, 2H), 5.7 (ddd, 1H, J=6.4 Hz, J=10.1 Hz, J=17.2 Hz), 5.30–5.17 (m, 2H), 4.45 (br, 1H), 3.66–3.55 (m, 3H), 3.23 (dt, 1H, J=3.1 Hz, J=11.9 Hz), 2.57 (dd, 1H, J=3.1 Hz, J=11.5 Hz), 2.47–2.43, (m, 1H), 2.47 (s, 3H), 2.40 (s, 3H).

By a method similar to Example 155, the following examples were prepared:

No.: X Data 156 4-OCH₃ Mass spectrum(electrospray): (m/z)=453.2(M+1); ¹H NMR: δ7.65–7.60(m, 4H), 7.00–6.89(m, 4H), 5.75(ddd, 1H, J=6.3Hz, J=10.5Hz, J=17.4Hz), 5.30– 5.19(m, 2H), 4.44(br, 1H), 3.89(s, 3H), 3.85(s, 3H), 3.63–3.53(m, 3H), 3.23(dt, 1H, J=3.0Hz, J=12.0Hz), 2.56(dd, 1H), J=3.7Hz, J=11.5Hz), 2.40(dt, 1H, J=3.1Hz, J=11.3Hz). Chiral HPLC: Chiralpak AD (0.46 × 25 cm), IPA:Heptane = 40:60, 1 mL/min, Retention Time: 21.00, 25.9 min. 157 2,4,6-tri- Mass spectrum(electrospray): (m/z)=477.3(M+1); methyl ¹H NMR (CDCl₃): δ6.95(s, 4H), 5.83–5.72(m, 1H), 5.16–5.00(m, 2H), 4.40(br, 1H), 3.47–3.28(m, 4H), 3.14(dd, 1H, J=3.5Hz, J=11.9Hz), 2.83(dt, 1H, J=3.8Hz, J=11.1Hz), 2.59(s, 12H), 2.30(s, 6H). Chiral HPLC: Chiralpak AD(0.46 × 25 cm), IPA:Heptane = 20:80, 1 mL/min, Retention Time: 8.43, 9.05 min. 158 2-NO₂ Mass spectrum(electrospray): (m/z)=483.1(M+1; ¹H NMR (CDCl₃): δ8.07–8.04(m, 1H), 7.94– 7.91(m, 1H), 7.74–7.60(m, 6H), 5.83(m, 1H), 5.32–5.22(m, 2H), 4.63(br, 1H), 3.95–3.71(m, 3H), 3.49(dt, 1H, J=3.2Hz, J=11.9Hz), 3.15(dt, 1H, J=3.7Hz, J=12.7Hz), 2.86(dt, 1H, J=3.4Hz, J=12.2Hz). Chiral HPLC: Chiralpak AD(0.46 × 25 cm), 100% EtOH, 1 mL/min, Retention Time: 8.92, 10.67 min.

By a method similar to Example 155, the following asymmetric products were obtained using (dba)₃Pd₂CHCl₃,(26 mg, “Pd”:0.05 mmol), (R)-BINAP (31.2 mg, 0.05 mmol), 1,2-bis(p-toylsulfonylamini)ethane(368 mg, 1.0 mmol) and (Z)-1,4-bis(methoxycarbonyloxy)but-2-ene (204 mg, 1.0 mmol).

No.: X Yield % ee % 159 p-Me 84 74.9(S) 160 p-OMe 85 73.9 161 2,4,6-TriMe 70 77.0 162 2-NO₂ 39 65.3

Example 163 2-Phenethyl-1,4-bis-(toluene-4-sulfonyl)-piperazine

Add 9-BBN (0.5 M THF solution, 13.7 mL, 6.85 mmol) to a 100 mL schlenk flask containing (S)-1,4-bis(toluene-4-sulfonyl)-2-vinyl-piperazine(0.96 g, 2.3 mmol) in THF (5 mL), at room temperature under nitrogen and stir. After 18 hours, treat the reaction with tetrakis(triphenylphosphine) palladium (53 mg, 0.046 mmol), triphenyl phosphine (94.6 mg, 0.36 mmol), iodiobenzene (0.703 g, 3.4 mmol) and 3N NaOH (2.8 mL, 8.4 mmol) and heat to reflux. After 24 hours, cool the reaction to room temperature, remove in vacuo the THF solvent, dilute the residue with CH₂Cl₂, wash with 1N HCl, brine, and dry over Na₂SO₄. Purification by flash chromatography twice (Gradient: Hexanes/CH₂Cl₂=50/50, to Hexanes/CH₂Cl₂/EtOAc=40/40/10), and recrystallization in MeOH gives 860 mg (75%) of the title compound: mass spectrum (electrospray): (m/z)=499.2 (M+1); ¹H NMR (CDCl₃): δ7.58–7.54 (m, 4H), 7.33–7.20 (m, 7H), 7.19–7.07 (m, 2H), 3.99 (m, 1H), 3.81–3.78 (m, 1H), 3.64–3.60 (m, 2H), 3.22 (dt, 1H, J=3.2 Hz, J=12.4 Hz), 2.57–2.41 (m, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 2.33–2.20 (m, 2H), 2.03–1.98 (m, 1H), 1.75–1.63 (m, 1H).

Example 164 2-Phenethyl-piperazine

Add 2-phenethyl-1,4-bis-(toluene-4-sulfonyl)-piperazine (100 mg, 0.2 mmol) in THF (2 mL) to a cooled (−78° C.) suspension of metallic Na (36.8 mg, 1.6 mmol) and naphthalene (230.4 mg, 1.8 mmol) in fresh distilled THF(4 mL) was under nitrogen and stir at −78° C. After 1 hour, TLC indicated the reaction is complete. Hydrolyze the reaction with brine (10 mL) and extract with CH₂Cl₂ (3×10 mL). Combine the organic layers and dry over Na₂SO₄ and evaporate. Pass the resulting residue through a SCX column to obtain the title compound as a solid: mass spectrum (electrospray): (m/z)=191.2 (M+1); ¹H NMR (CDCl₃): δ7.30–7.25 (m, 2H), 7.20–7.15 (m, 3H), 3.00–2.61 (m, 8H), 2.40 (t, 1H, J=11.7 Hz), 1.70 (br, 2H), 1.67–1.60 (m, 2H).

Example 171 (S)-1,4-Dibenzyl-2-phenethyl-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (4.9 g, 16.63 mmol) and 9-borabicyclo[3.3.1]nonane (199.6 ml, 99.78 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add iodo-benzene (5.1 g, 24.95 mmol), triphenylphosphine (697.9 mg, 2.66 mmol), tetrakis(triphenylphosphine) palladium(0)(384.3 mg, 0.33 mmol), and 3N NaOH (13.7 mL) and stir at 60° C. After 22 hours, dilute the mixture with ethyl acetate and wash it with 1N sulfuric acid. Adjust the pH to 14, extract with ethyl acetate, and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a ethyl acetate/hexanes gradient (5:95 to 10:90) to give (5.15 g, 84%) of the title compound as a white solid: mp 86–90° C.; mass spectrum (ion spray): m/z=371.3 (M+1).

Example 172 (S)-1,4-Dibenzyl-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.5 g, 8.55 mmol) and 9-borabicyclo[3.3.1]nonane (68.4 mL, 34.20 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add 1-iodo-2-methoxy-benzene (3.0 g, 12.82 mmol), triphenylphosphine (358.8 mg, 1.37 mmol), tetrakis(triphenylphosphine) palladium(0) (197.5 mg, 0.17 mmol), and 3N NaOH (7.0 mL) and stir at 60° C. After 22 hours, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using ethyl acetate/hexanes (5:95) to give (2.21 g, 65%) of the title compound: mp 58–61 C°; mass spectrum (ion spray): m/z=401.3 (M+1); Analysis for C₂₇H₃₂N₂O: calcd: C, 80.96; H, 8.05; N, 6.99; found: C, 81.08; H, 7.99; N, 7.10.

Example 173 (S)-2-(2-(4-Methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(4-methoxy-phenyl)-ethyl)-piperazine (1.34 g, 3.33 mmol), ammonium formate (1.05 g, 16.67 mmol), 5% Pd/C (161.2 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give (689.3 mg, 94%) of the title compound as a white solid: mp 125–130° C.; mass spectrum (ion spray): m/z=221.1 (M+1); Analysis for C₁₃H₂₀N₂O: calcd: C, 70.87; H, 9.15; N, 12.72; found: C, 70.58; H, 9.05; N, 12.61.

Example 174 (S)-2-(2-(3-Methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(3-methoxy-phenyl)-ethyl)-piperazine (2.15 g, 5.37 mmol), ammonium formate (1.69 g, 26.84 mmol), 5% Pd/C (259.7 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/7N ammonia in methanol (90:10) to give (1.11 g, 94%) of the title compound as a white solid: mp 53–57° C.; mass spectrum (ion spray): m/z=221.1 (M+1); Analysis for C₁₃H₂₀N₂O: calcd: C, 70.87; H, 9.15; N, 12.72; found: C, 70.52; H, 9.06; N, 12.74.

Example 175 (S)-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine (2.10 g, 5.24 mmol), ammonium formate (1.65 g, 26.19 mmol), 5% Pd/C (253.6 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give (1.00 g, 87%) of the title compound: mass spectrum (ion spray): m/z=221.1 (M+1).

Example 176 10-((S)-3-(2-(4-Fluorophenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (492.9 mg, 1.85 mmol), (S)-2-(2-(4-fluoro-phenyl)-ethyl)-piperazine (772.6 mg, 3.71 mmol), N,N-diisopropylethylamine (239.7 mg, 1.85 mmol), DMSO (0.82 ml), and toluene (3.3 mL). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (376.0 mg, 48%) of a brown foam. Prepare the dihydrochloride salt in ethyl acetate: mp 236° C., dec; mass spectrum (ion spray): m/z=421.2 (M+1).

Example 177 10-((S)-3-(2-(3-Fluoro-phenyl)-ethyl)-piperazin-1-yl))-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (696.7 mg, 2.62 mmol), (S)-2-(2-(3-fluoro-phenyl)-ethyl)-piperazine (1.09 g, 5.24 mmol), N,N-diisopropylethylamine (338.8 mg, 2.62 mmol), DMSO (1.2 ml), and toluene (4.6 mL). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (526.8 mg, 48%) of a dark brown oil. Prepare the dihydrochloride salt in ethyl acetate: mp 211° C., dec; mass spectrum (ion spray): m/z=421.2 (M+1).

Example 178 10-((S)-3-(2-(2-Fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (645.8 mg, 2.43 mmol), (S)-2-(2-(2-fluoro-phenyl)-ethyl)-piperazine (1.01 g, 4.86 mmol), N,N-diisopropylethylamine (314.1 mg, 2.43 mmol), DMSO (1.1 ml), and toluene (4.3 mL). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (481.7 mg, 47%) of a brown foam. Prepare the dihydrochloride salt in ethyl acetate: mp 209°, dec; mass spectrum (ion spray): m/z=421.2 (M+1).

Example 179 10-((S)-3-(2-(4-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (620.0 mg, 2.33 mmol), (S)-2-(2-(4-methoxy-phenyl)-ethyl)-piperazine (1.03 g, 4.67 mmol), N,N-diisopropylethylamine (301.5 mg, 2.33 mmol), DMSO (1.0 mL), and toluene (4.0 mL). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (703.8 mg, 70%) of a brown oil. Prepare the dihydrochloride salt in ethyl acetate: mp 213° C., dec; mass spectrum (ion spray): m/z=433.1 (M+1).

Example 180 10-((S)-3-(2-(3-Methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (301.6 mg, 1.13 mmol), (S)-2-(2-(3-methoxy-phenyl)-ethyl)-piperazine (500.0 mg, 2.27 mmol), N,N-diisopropylethylamine (146.7 mg, 1.13 mmol), DMSO (0.5 mL), and toluene (2.0 mL). Stir and heat the mixture at 105° C. After 64 hours, cool the mixture to ambient temperature and then dilute it with acetic acid/methanol (1:9) and apply it to an SCX column. Wash the column with methanol to remove impurities. Treat the column with 7N ammonia in methanol to elude the product. Evaporate the solvent to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (279.0 mg, 57%) of a brown foam. Prepare the dihydrochloride salt in ethyl acetate: mp 201° C., dec; mass spectrum (ion spray): m/z=433.3 (M+1).

Example 181 10-((S)-3-(2-(2-Methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.17 g, 4.42 mmol), (S)-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine (973.5 mg, 4.42 mmol), N,N-diisopropylethylamine (571.1 mg, 4.42 mmol), DMSO (2.0 mL), and toluene (8.0 mL). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (473.9 mg, 25%) of a brown foam. Prepare the dihydrochloride salt in ethyl acetate: mp 202° C., dec; mass spectrum (ion spray): m/z=433.1 (M+1).

Example 182 10-((S)-3-(2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 10-((S)-3-(2-(4-fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (259.0 mg, 0.62 mmol), formaldehyde (55.0 μL, 0.68 mmol, 37% in water), and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (195.8 mg, 0.92 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (236.7 mg, 89%) of a brown foam. Prepare the dihydrochloride salt in ethyl acetate: mp 253° C., dec; mass spectrum (ion spray): m/z=435.1 (M+1).

Example 183 10-((S)-3-(2-(3-Fluoro-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 10-((S)-3-(2-(3-fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (265.6 mg, 0.63 mmol), formaldehyde (56.4 μL, 0.69 mmol, 37% in water), and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (200.7 mg, 0.95 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (215.4 mg, 79%) of a brown oil. Prepare the dihydrochloride salt in ethyl acetate: mp 225° C., dec; mass spectrum (ion spray): m/z=435.1 (M+1).

Example 184 10-((S)-3-(2-(2-Fluoro-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 10-((S)-3-(2-(2-fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (240.0 mg, 0.57 mmol), formaldehyde (50.9 μL, 0.63 mmol, 37% in water), and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (181.4 mg, 0.86 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (247.9 mg, 100%) of a brown oil. Prepare the dihydrochloride salt in ethyl acetate: mp 203° C., dec; mass spectrum (ion spray): m/z=435.3 (M+1).

Example 185 10-((S)-3-(2-(4-Methoxy-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 10-((S)-3-(2-(4-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (159.2 mg, 0.37 mmol), formaldehyde (32.9 μL, 0.41 mmol, 37% in water), and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (117.0 mg, 0.55 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (158.4 mg, 96%) of a brown foam. Prepare the dihydrochloride salt in ethyl acetate: mp 239° C., dec; mass spectrum (ion spray): m/z=447.2 (M+1).

Example 186 10-((S)-3-(2-(3-Methoxy-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4.9-diaza-benzo[f]azulene dihydrochloride

Combine 10-((S)-3-(2-(3-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (279.0 mg, 0.65 mmol), formaldehyde (57.6 μL, 0.71 mmol, 37% in water), and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (205.0 mg, 0.97 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (278.7 mg, 97%) of a brown oil. Prepare the dihydrochloride salt in ethyl acetate:mp 200° C., dec; mass spectrum (ion spray): m/z=447.1 (M+1).

Example 187 10-((S)-3-(2-(2-Methoxy-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Combine 10-((S)-3-(2-(2-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (209.2 mg, 0.48 mmol), formaldehyde (43.2 μL, 0.53 mmol, 37% in water), and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (153.7 mg, 0.73 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give (191.6 mg, 89%) of a brown foam. Prepare the dihydrochloride salt in ethyl acetate: mp 213° C., dec; mass spectrum (ion spray): m/z=447.2 (M+1).

Example 188 2-Methyl-10-(4-methyl-(S)-3-(2-pyridin-4-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene trihydrochloride hydrate

Combine 2-methyl-10-((S)-3-(2-pyridin-4-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene (380 mg, 0.94 mmol) and formaldehyde (82 μL, 1.04 mmol, 37% in water), and methylene chloride (10 mL). Stir 5 minutes at ambient temperature. Add sodium triacetoxyborohydride (300 mg, 1.41 mmol) and stir 30 minutes at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–3%) as the eluent to give 345 mg of a brown foam. Purify again by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0%–6.5%) as the eluent to give the free base. Crystallize as the trihydrochloride salt from ethyl acetate and ethanol to give the title compound (244 mg, 62%): mp 214–217° C. dec.; mass spectrum (ion spray): m/z=418 (M+1), 416 (M−1). Analysis calculated for C₂₄H₂₇N₅S.3HCl·0.9H₂O: C, 53.07; H, 5.90; N, 12.89. Found: C, 53.31; H, 5.54; N, 12.75.

Example 189 2-Methyl-10-((S)-3-(2-pyridin-3-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene trihydrochloride dihydrate

Combine (S)-2-(2-pyridin-3-yl-ethyl)-piperazine (2.0 g, 10.5 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (2.4 g, 10.5 mmol), acetic acid (0.1 mL), toluene (21 mL), and DMSO (5 mL). Heat at 110° C. Purge periodically with nitrogen and replace condensor after 4 hours. After 41 hours 30 minutes, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0%–5%) as the eluent to give the free base. Purify 600 mg by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give the free base. Crystallize as the trihydrochloride salt from ethyl acetate and ethanol to give the title compound: mp 226–229° C. dec.; mass spectrum (ion spray): m/z=404 (M+1), 402 (M−1). Analysis calculated for C₂₃H₂₅N₅S.3HCl.2H₂O: C, 50.32; H, 5.88; N, 12.76. Found: C, 50.32; H, 5.97; N, 12.71.

Example 190 2-Methyl-10-(4-methyl-(S)-3-(2-pyridin-3-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-10-((S)-3-(2-pyridin-3-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene (728 mg, 1.80 mmol) and formaldehyde (158 μL, 1.98 mmol, 37% in water), and methylene chloride (30 mL). Stir 10 minutes at ambient temperature. Add sodium triacetoxyborohydride (573 mg, 2.70 mmol) and stir 1 hour at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0%–4%) as the eluent to give the title compound (595 mg, 79%): Mass spectrum (ion spray): m/z=418 (M+1), 416 (M−1). Analysis calculated for C₂₄H₂₇N₅S: C, 69.03; H, 6.52; N, 16.77. Found: C, 68.92; H, 6.60; N, 16.65.

Example 191 2-Methyl-10-(4-methyl-(S)-3-(2-pyridin-2-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene trihydrochloride

Combine 2-methyl-10-((S)-3-(2-pyridin-2-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene (200 mg, 0.50 mmol) and formaldehyde (43 μL, 0.54 mmol, 37% in water), and methylene chloride (5 mL). Stir 10 minutes at ambient temperature. Add sodium triacetoxyborohydride (158 mg, 0.74 mmol) and stir 1 hour at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0%–4%) as the eluent to give the free base. Crystallize as the trihydrochloride salt from ethyl acetate and ethanol to give the title compound (161 mg, 78%): Mass spectrum (ion spray): m/z=418 (M+1), 416 (M−1). Analysis calculated for C₂₄H₂₇N₅S.3HCl: C, 54.70; H, 5.74; N, 13.29. Found: C, 54.88; H, 6.02; N, 12.96.

Example 192 (S)-1,4-Dibenzyl-2-(4-phenyl-but-3-enyl)-piperazine

Combine 9-borabicyclo[3.3.1]nonane (81.6 mL, 40.3 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.8 mmol)and stir at ambient temperature. After 16 hours, take half volume of it, add triphenylphosphine (143 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (78.5 mg, 0.068 mmol), and beta-bromostyrene (0.93 g, 5.08 mmol). Add 3N NaOH (2.8 mL, 8.8 mmol) slowly, gas evolution will occur. Heat to reflux. After 24 hours, cool to ambient temperature. Remove the solvent under reduced pressure, dilute with diethyl ether, wash with 1N HCl, 1N NaOH, H₂O and brine, dry the organic layer over Na₂SO₄, filter and concentrate under reduced pressure. Purification by flash chromatography on silica gel using 2N ammonia in methanol-methylene chloride (0.5%–3%) as the eluent, collect compound and pass through 10 g SCX column, using MeOH, 0.2 N NH₃ in MeOH as eluent to give the title compound (750 mg, 56%): mass spectrum (electrospray): m/z=397.3 (M+1); ¹H NMR (300 MHz, CDCl₃): δ7.35–7.16 (m, 15H), 6.36–6.12 (m, 2H), 4.01 (d, 1H, J=13.2), 3.56–3.43 (m, 2H), 3.25 (d, 1H, J=13.4 Hz), 2.75–2.68 (m, 2H), 2.56–2.48 (m, 2H), 2.29–2.13 (m, 5H), 1.82–1.76 (m, 2H).

Example 193 (S)-2-(4-Phenyl-butyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(4-phenyl-but-3-enyl)-piperazine (2.12 g, 5.3 mmol), 10% Pd/C (300 mg, 0.027 mmol) and ammonia formate (1.67 g, 26.5 mmol) in EtOH (50 mL), heat to reflux for 3 hours 30 minutes, and cool to room temperature. Remove the catalyst via filtration, and concentrate the filtrate to a residue. Purification by flash chromatography on silica gel using 2N NH₃ in MeOH and dichloromethane (5%–15%) to give the title compound (780 mg, yield 67%): mass spectrum (Electrospray): m/z=219.2 (M+1); ¹H NMR (CDCl₃): δ7.30–7.15 (m, 5H), 2.96–2.55 (m, 8H), 2.37–2.30 (m, 1H), 1.64–1.60 (m, 2H), 1.39–1.29 (m, 4H).

Example 194 (S)-2-Methyl-10-(3-(4-phenyl-butyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene, dihydrochloric acid

Combine (S)-2-(4-phenyl-butyl)-piperazine (820 mg, 3.76 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (861 mg, 3.76 mmol), 1-methyl-2-pyrrolidinone (7 mL), and heat at 220° C. After 4 hours, cool to ambient temperature, pass through SCX column (10 G), and collect the fraction of 0.2 NH₃ in methanol. Purification by silica gel chromatography of the crude product using 2N ammonia in methanol-dichloromethane (2%–4%) as the eluent to give 310 mg brown foam of the free base: mass spectrum (Electronspray): m/z=431.3 (M+1); ¹H NMR (300 MHz, CDCl₃): δ7.30–7.15 (m, 5H), 7.04–6.84 (m, 3H), 6.60 (dd, 1H, J=1.3, J=7.7 Hz), 6.28 (d, 1H, J=1.2 Hz), 4.95 (s, 1H), 4.06–3.96 (m, 2H), 3.05–2.89 (m, 2H), 2.77–2.74 (m, 1H), 2.65–2.49 (m, 3H), 2.30 (d, 3H, J=1.1 Hz), 1.64 (m, 2H), 1.45–1.37 (m, 4H). Pass this product through a SCX column (5 g), eluent with 0.6 M CH₃COCl/EtOH, concentrate to give yellow foam, treat with 15 mL of CH₃CN/H₂O=50/50, and lyophilize overnight to give yellow gold solid of title compound: mass spectrum (Electrospray): m/z=431.1 (M+1–2HCl, 429.1 (M−1–2HCl); Analysis calculated for C₂₆H₃₀N₄S.2HCl.1.6 H₂O: C, 58.66; H, 6.66; N, 10.52. Found: C, 58.34; H, 6.47; N, 10.16.

Example 195 (S)-2-Methyl-10-(3-(4-phenyl-butyl)-4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene, dihydrochloric acid

Combine (S)-2-methyl-10-3-(4-phenyl-butyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (230 mg, 0.53 mmol), formaldehyde (37% aq, 47 mg, 0.58 mmol) and sodium triacetoxyborohydride (168.5 mg, 0.795 mmol) in 1,2-dichloroethane (15 mL) and stir at room temperature. After 2 hours, quench the reaction by adding sat. NaHCO₃, extract the aqueous solution with CH₂Cl₂ (3×10 mL), wash the organic solvent with brine and dry over Na₂SO₄. Concentrate the solvent in vaccuo to give a residue and purify by silica gel chromatography using 2N ammonia in methanol-dichloromethane (2%–4%) as the eluent to give (170 mg, 72%) light brown foam of the free base: mass spectrum (Electrospray): m/z=445.2 (M+1); ¹H NMR (400 MHz, CDCl₃): δ7.29–7.15 (m, 5H), 7.03–6.85 (m, 3H), 6.60 (dd, 1H, J=1.5, J=7.8 Hz), 6.28 (d, 1H, J=1.0 Hz), 4.95 (s, 1H), 3.98–3.85 (m, 2H), 3.15–3.08 (m, 1H), 2.86–2.75 (m, 3H), 2.64–2.59 (m, 2H), 2.36–28 (m, 8H), 2.10–2.04 (m, 1H), 1.66–1.35 (m, 4H). Treat the free base with acetyl chloride (2.2 eq) in ethanol for 1hour 30 minutes at room temperature, remove the solvent, dissolve in solvent (15 mL) CH₃CN/H₂O=50/50, lyophilize overnight to give yellow solid of title compound: mass spectrum (Electrospray): m/z=445.2 (M+1–2HCl), 443.2 (M−1–2HCl). Analysis calculated for C₂₇H₃₂N₄S.2HCl.0.6 H₂O: C, 61.38; H, 6.71; N, 10.60. Found: C, 61.38; H, 6.44; N, 10.54.

Example 196 (S)-4-Benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester

Dissolve commercial N-tBoc-L-aspartic acid beta-methyl ester (40 g, 0.16 moles) in dichloromethane (800 mL); cool to 0° C. and add N-benzylglycine methyl ester (28 g, 0.15 moles) as a solution in 100 mL of dichloromethane, followed sequentially by N,N-diisopropylethylamine (28 mL, 0.16 moles), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC, 31 g, 0.16 moles), and 1-hydroxybenzotriazole (22 g, 0.16 moles). Stir at room temperature over the weekend; then concentrate in vacuo to an orange oil. Partition the oil between 2N hydrochloric acid and ethyl acetate; separate aqueous layer and extract with a second portion of ethyl acetate. Combine organic extracts, concentrate in vacuo, and wash with 10% aqueous potassium carbonate. Dry organic layer over magnesium sulfate, filter and concentrate in vacuo to yield 64 g (95%) of the desired dipeptide as an oily residue. Dissolve the crude dipeptide in 150 mL of trifluoroacetic acid, stir at room temperature for 1 h; then remove the solvent in vacuo. Take up the resulting residue on 800 mL of commercial 2N ammonia in methanol solution, and stir at room temperature overnight. Heat the mixture at 70° C. for several hours; then cool to room temperature and remove the solvent in vacuo. Redissolve the residue in dichloromethane, filter off the resulting precipitate, and concentrate the filtrate in vacuo. Apply the residue to a silica gel column. Elute with a 2% mixture of 2N ammonia-methanol in dichloromethane to obtain 31.9 g (72%) of S-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acid methyl as a yellow oil.

To a 0° C. solution of S-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acid methyl ester (31.9 g, 0.12 moles) in tetrahydrofuran (1 L), add lithium aluminum hydride via slow cannulation (350 mL of a commercial 1.0 M solution in tetrahydrofuran). Stir at room temperature overnight, quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxide, and 39.9 mL of water, all the while with vigourous stirring to ensure formation of a fine precipitate. Filter through a fritted funnel, washing the solids well with tetrahydrofuran and dichloromethane. Concentrate in vacuo to provide 26.5 g of an oily residue, apply directly to a silica gel column. Elute with a 5% mixture of 7N ammonia-methanol in dichloromethane, to obtain the desired product as an orange oil which solidifies under vacuum. Take up the solid in acetonitrile and sonicate for a few minutes. Filter the resulting precipitate to obtain 7.5 g (25%) of S-(−)-2-(4-benzylpiperazin-2-yl)ethanol as an off-white crystalline solid, mp 78.9–80.4° C. Concentrate the mother liquor to obtain 6.8 g (23%) of slightly less pure material as an amorphous solid

Combine (S)-2-(4-benzylpiperazin-2-yl)ethanol (3.08 g, 14.0 mmol) in methylenechloride (30 mL) and di-tert-butyl dicarbonate (3.2 g, 14.7 mmol) in 5 mL CH₂Cl₂ and add dropwise at room temperature. After 1 hour, quench the reaction mixture by adding water, extract with CH₂Cl₂, wash with water and brine, and dry over Na₂SO₄. Purification by silica gel chromatography of the crude product by using MeOH/CH₂Cl₂ (5% to 10%) as the eluent, gives 3.17 g (Yield 71%) of title compound: ¹H NMR (400 MHz, CDCl₃): δ7.37–7.23 (m, 5H), 4.27–4.10 (m, 1H), 4.02–3.80 (m, 211), 3.61–3.23 (m, 4H), 3.00 (t, 1H, J=10 Hz), 2.71–2.56 (m, 2H), 2.24–2.22 (m, 2H), 2.01 (dt, 1H, J=3.4, 12.2 Hz), 1.46 (s, 9H).

Example 197 (S)-4-Benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl ester

Add dichloromethane (3 mL) to a 50 mL dry schlenk flask, followed by oxalyl chloride (0.178 g, 1.4 mmol) and cool the solution to −78° C. and treat with dimethyl sulfoxide (0.171 g, 2.2 mmol) and triethylamine (0.505 g, 5.0 mmol). After 10 min, add a solution of (S)-4-benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.320 g, 1.0 mmol) in dichloromethane (5 mL) and stir the resulting mixture at −78° C. for 1 hour. Quench the reaction mixture by adding sat. NaHCO₃, extract the aqueous solution with CH₂Cl₂, wash the organic solvent with brine, and dry over Na₂SO₄. Purification by silica gel chromatography of the crude product using MeOH/CH₂Cl₂ (5% to 10%) as eluent to give the title compound (160 g, 50%) as a light yellow oil: mass spectrum (Electrospray): m/z=319.2 (M+1); ¹H NMR (400 MHz, CDCl₃): δ9.74 (t, 1H, J=2.0 Hz), 7.33–7.21 (m, 5H), 4.57 (br, 1H), 3.88 (m, 2H), 33.52–3.40 (m, 21H), 3.15–3.05 (m, 1H), 2.83–2.66 (m, 4H), 2.22–2.18 (m, 1H), 2.03 (dt, 1H, J=3.4, 11.8 Hz), 1.44 (s, 9H).

Example 198 (S)-4-Benzyl-2-(3-phenyl-allyl)-piperazine-1-carboxylic acid tert-butyl ester

Combine and cool to 0° C. a solution of (S)-4-benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.95 g, 6.13 mmol) and diethyl benzyl phosphonate (4.23 g, 18.55 mmol) in dry DMF (25 mL), and add solid sodium methoxide (95%, 1.15 g, 21.3 mmol) in a single portion, and stir at 0° C. for 30 minutes. Dilute the mixture with CH₂Cl₂, wash with brine and dry the organic layer over Na₂SO₄. Purification by silica gel chromatography of the crude product using EtOAC/CH₂Cl₂ (2% to 10%) as eluent gives the title compound (2.37 g) as a white solid: mass spectrum (Electrospray): m/z=393.3 (M+1); ¹H NMR (400 MHz, CDCl₃): δ7.37–7.21 (m, 10H), 6.34–6.30 (m, 1H), 6.12–6.02 (m, 1H), 4.10 (br, 1H), 3.87 (br, 1H), 3.59–3.52 (m, 1H), 3.41–3.35 (m, 1H), 3.13 (m, 1H), 2.82–2.59 (m, 4H), 2.18–2.04 (m, 2H), 1.39 (s, 9H).

Example 199 (S)-1-Benzyl-3-(3-phenyl-allyl)-piperazine

Dissolve (S)-4-benzyl-2-(3-phenyl-allyl)-piperazine-1-carboxylic acid tert-butyl ester (2.37 g, 6.04 mmol) in toluene (50 mL) and treat with trifluoroacetic acid (10.3 g, 90.5 mmol) at room temperature, and stir the reaction mixture. After overnight, dilute the reaction with CH₂Cl₂, and basify with 2N NaOH (50 mL), extract the aqueous solution with CH₂Cl₂, wash the combined organic layers brine, dry over Na₂SO₄. Pass the crude product through a SCX column (10 g), collect the 0.2N NH₃/MeOH eluent and concentrate to give 1.46 g of the title compound: mass spectrum (Electrospray): m/z=293.3 (M+1). ¹H NMR (400 MHz, CDCl₃): δ7.35–7.19 (m, 10H), 6.54–6.47 (m, 1H) 6.18–6.11, 5.70–5.60 (m, 1H), 3.70 (s, 2H), 2.97–2.73 (m, 5H), 2.40–2.18 (m, 2H), 2.09–2.00 (m, 1H), 1.83 (t, 1H, J=9.8 Hz).

Example 200 (S)-2-(3-Phenyl-propyl)-piperazine

Combine (S)-1-benzyl-3-(3-phenyl-allyl)-piperazine (1.45 g, 5.0 mmol), 10% Pd/C (265 mg, 0.025 mmol) and ammonia formate (1.57 g, 25.0 mmol) in EtOH (90 mL) and heat to reflux for 3 hours, cool to room temperature, remove the catalyst by filtration. Concentrate the solvent to a residue, which ¹H NMR shows that the carbon-carbon double bond has been reduced, but the benzyl group remains. Subject the residue to the reaction with 10% Pd(OH)₂/C (350 mg, 0.5 mmol) in EtOH with a balloon of hydrogen under reflux conditions. After refluxing for 3 hours, cool the reaction to room temperature, remove the catalyst, concentrate to a residue, and purification by silica gel chromatography using 2N NH₃ in MeOH and dichloromethane (5%–15%) to give the title compound (950 mg, 93%): mass spectrum (Electrospray): m/z=205.2 (M+1); ¹H NMR (CDCl₃): δ7.29–7.15 (m, 5H), 2.97–2.59 (m, 6H), 2.35 (t, 1H, J=9.8 Hz), 1.70–1.45 (m, 6H), 1.38–1.25 (m, 2H).

Example 201 (S)-2-Methyl-10-(3-(3-phenyl-propyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene, dihydrochloric acid

Combine (S)-2-(3-phenyl-propyl)-piperazine (510 mg, 2.50 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (663 mg, 2.50 mmol), diisopropylethylamine (4 mL), DMSO/Toluent (1.25/2.5 mL), heat at 110° C. After 24 hours, cool to ambient temperature, remove the solvent, dilute with CH₂Cl₂, wash with water, brine, and dry over with Na₂SO₄. Purification by silica gel chromatography of the crude product using 2N ammonia in methanol-methylene chloride (2–4%) as the eluent gives 310 mg brown foam of the free base: mass spectrum (Electrospray): m/z=417.3 (M+1). ¹H NMR (400 MHz, CDCl₃): δ7.31–7.23 (m, 2H), 7.20–7.15 (m, 3H), 7.04–6.85 (m, 3H), 6.60 (dd, 1H, J=1.5, J=7.8 Hz), 6.28 (d, 1H, J=1.5 Hz), 4.94 (s, 1H), 4.07–3.96 (m, 2H), 3.05–2.89 (m, 3H), 2.79–2.77 (m, 1H), 2.64 (t, 2H, J=7.3 Hz), 2.57–2.51 (m, 1H), 2.29 (d, 3H, J=1.0 Hz), 1.76–1.40 (m, 5H). Treat the free base with NH₄Cl (2.0 eq.) in MeOH, remove the solvent, dissolve in CH₃CN/H₂O=50/50, lyophilize overnight to give the title compound as a yellow solid: mass spectrum (Electrospray): m/z=417.1 (M+1–2HCl), 416.1 (M−1–2HCl).

Example 202 (S)-2-Methyl-10-(3-(3-phenyl-propyl)-4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene,dihydrochloric acid

Combine (S)-2-methyl-10-3-(3-phenyl-propyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (320 mg, 0.77 mmol), formaldehyde (37% aq, 68.6 mg, 0.85 mmol) and sodium triacetoxyborohydride (244.7 mg, 1.15 mmol) in 1,2-dichloroethane (15 mL) and stir at room temperature. After 4 hours, quench the reaction adding sat. NaHCO₃, extract the aqueous solution with CH₂Cl₂ (3×10 mL), wash the organic solvent with brine, and dry over Na₂SO₄. Concentrate the solvent in vaccuo to give a residue and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2–4%) as the eluent to give 285 mg (yield 86%) light brown foam of the free base: mass spectrum (Electrospray): m/z=431.3 (M+1); ¹H NMR (400 MHz, CDCl₃): δ7.29–7.16 (m, 5H), 7.03–6.85 (m, 3H), 6.59 (dd, 1H, J=1.5, J=7.8 Hz), 6.28 (d, 1H, J=1.0 Hz), 4.94 (s, 1H), 3.99–3.89 (m, 2H), 3.14–3.09 (m, 1H), 2.85–2.77 (m, 2H), 2.68–2.56 (m, 2H), 2.35–2.14 (m, 8H), 1.74–1.42 (m, 4H). Analysis calculated for C₂₆H₃₀N₄S.0.3H₂O: C, 71.62; H, 7.07; N, 12.86. Found: C, 71.69; H, 6.94; N, 12.48. Treat the free base with ammonia chloride (2.0 eq.) in MeOH at 45° C. for 1 hour, remove the solvent, dissolve in a mix solvent (15 mL) CH₃CN/H₂O=50/50, lyophilize overnight to give the title compound as a yellow solid.

By a method similar to Example 59, using the appropriate starting materials, the following compounds were prepared and isolated as the (S) isomer except where noted below:

No: ArAlk Data 209 CH₂(4-Br)Ph mp 97–112° C.: ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.59(dd, 1H), 2.65(dd, 1H), 2.74(dd, 1H), 2.88–2.80(m, 1H), 3.03–2.91(m, 3H), 3.99(d, 1H), 4.07(d, 1H), 4.97(s, 1H), 6.17(t, 1H), 6.59(dt, 1H), 6.87(ddd, 1H), 6.97(ddd, 1H), 7.11(d, 2H), 7.43(d, 2H); MS(APCI)m/z(rel intensity)468.3(96), 469.3(100). 57% yield. 210 CH₂(4-I)Ph mp 105–121° C.: ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.58(dd, 1H), 2.66(dd, 1H), 2.73(dd, 1H), 2.88–2.80(m, 1H), 3.03–2.91(m, 3H), 3.99(d, 1H), 4.07(d, 1H), 4.97(s, 1H), 6.17(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H), 7.03–6.94(m, 4H), 7.63(d, 2H); MS(APCI)m/z(rel intensity)515.4(100). 47% yield. 211 CH₂(4-O—CH₂CH₂═CH₂)Ph ¹H NMR(CD₃OH): δ2.17(bs, 3H), 2.87(m, 1H), 3.05(m, 1H), 3.39–3.50(m, 2H), 3.63–3.86(m, 3H), 4.07(m, 1H), 4.29(m, 1H), 4.55(m, 2H), 5.26(m, 1H), 5.40(m, 1H), 6.07(m, 1H), 6.25(bs, 1H), 6.88(d, 1H), 6.95(d, 2H), 7.12–7.28(m, 5H); MS(APCI)m/z(rel intensity)445(100). 10 mg product. 212 CH₂(thiophen-3-yl) mp 82–94° C.: ¹H NMR(CDCl₃): δ2.28(s, 3H), 2.67(dd, 1H), 2.70(dd, 1H), 2.81(dd, 1H), 2.87(dd, 1H), 3.06–2.93(m, 3H), 3.99(d, 1H), 4.11(d, 1H), 4.98(s, 1H), 6.23(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H), 6.97(dt, 1H), 6.99(dd, 1H), 7.02(dd, 1H), 7.05(m, 1H), 7.29(dd, 1H); MS(APCI)m/z(rel intensity 395.4(100). 47% yield. 213 CH₂(4-OiPr)Ph mp 106–119° C.: ¹H NMR(CDCl₃): δ1.32(d, 3H), 1.34(d, 3H), 2.26(d, 3H), 2.55(dd, 1H), 2.67(dd, 1H), 2.73(dd, 1H), 2.84(dd, 1H), 3.04–2.92(m, 3H), 4.00(d, 1H), 4.09(d, 1H), 4.51(qt, 1H), 4.94(s, 1H), 6.21(d, 1H), 6.60(dd, 1H), 6.84– 6.80(m, 2H), 6.87(dt, 1H), 6.96(dt, 1H), 7.01(dd, 1H), 7.14– 7.10(m, 2H); MS(APCI)m/z(rel intensity)447.5(100). 44% yield.

By a method similar to Example 1, using the appropriate starting materials, the following compounds were prepared and isolated as the(S) isomer except where noted below:

No.: ArAlk Data 214 CH₂(4-Br)Ph ¹H NMR(DMSO-d₆): δ2.87(dd, 1H), 3.01(d, 1H), 3.07(dd, 1H), 3.46(d, 1H), 4.08(m, 1H), 7.13(d, 2H), 7.48(d, 2H), 7.94(s, 1H), 8.17(s, 1H); MS(APCI)m/z (rel intensity)283(100). 285(100). 215 CH₂(4-I)Ph ¹H NMR(DMSO-d₆): δ2.84(dd, 1H), 2.97(d, 1H), 3.04(dd, 1H), 3.45(d, 1H), 4.06(m, 1H), 6.99(d, 2H), 7.64(2H, 1H), 7.93(s, 1H), 8.16(s, 1H); MS(APCI)m/z (rel intensity)331(100). 216 CH₂(thiophen-3-yl) mp 248–249° C.: ¹H NMR(DMSO-d₆): δ2.87(dd, 1H), 2.92(d, 1H), 3.09(dd, 1H), 3.42(dd, 1H), 4.01(m, 1H), 6.88(dd, 1H), 7.12(m, 1H), 7.42(m, 1H), 7.87(s, 1H), 8.10(s, 1H). 217 CH₂(4-iPrO)Ph mp 242° C.: ¹ H NMR(DMSO-d₆): δ1.24(d, 6H), 2.74(d, 1H), 2.80(dd, 1H), 3.03(dd, 1H), 3.34(d, 1H), 4.02(m, 1H), 4.57(septet, 1H), 6.81(d, 1H), 7.04(d, 1H), 7.87(s, 1H), 8.12(s, 1H). 217a CH₂(3,4-OCH₂O—)Ph mp 255–257° C.: ¹H NMR(DMSO-d₆) δ2.80(dd, 1H), 3.01(dd, 2H), 3.43(dd, 1H), 4.01(m, 1H), 5.98(s, 2H), 6.63(dd, 1H), 6.70(s, 1H), 6.83(d, 1H), 7.92(s, 1H), 8.09(d, 1H). 217b CH₂(3,4-Di-OCH₃)Ph mp 254–255° C.: ¹H NMR(DMSO-d₆) δ2.72(d, 1H), 2.78(dd, 1H), 2.98(dd, 1H), 3.33(dd, 1H), 3.65(s, 3H), 3.67(s, 3H), 3.99(m, 1H), 6.63(d, 1H), 6.71(s, 1H), 6.81(d, 1H), 7.82(s, 1H), 8.06(d, 1H).

By a method similar to Example 90, using the appropriate starting materials, the following compounds were prepared and isolated as the free base and as the (S) isomer except where noted:

No: ArAlk Data 218 CH₂(4-Br)Ph mp 68–79° C.: ¹H NMR(CDCl₃): δ2.17(s, 3H), 2.46–2.34(m, 3H), 2.48(s, 3H), 2.78(dd, 1H), 2.90(dt, 1H), 3.11(dd, 1H), 3.19(ddd, 1H), 3.56(d, 1H), 3.96(d, 1H), 4.91(s, 1H), 5.96(s, 1H), 6.57(dd, 1H), 6.85(ddd, 1H), 6.98–6.91(m, 2H), 7.06–7.02(m, 2H), 7.41–7.36(m, 2H); MS(APCI)m/z(rel intensity)482.3 (96), 483.3(100). 92% yield. 219 CH₂(thiophen-3-yl) mp 58–72° C.: ¹H NMR(CDCl₃): δ2.20(s, 3H), 2.48–2.37(m, 2H), 2.46(s, 3H), 2.58(dd, 1H), 2.78(dd, 1H), 2.89(dt, 1H), 3.11(dd, 1H), 3.19(ddd, 1H), 3.69(d, 1H), 3.97(d, 1H), 4.92(s, 1H), 6.06(s, 1H), 6.57(dd, 1H), 6.85(ddd, 1H), 7.00–6.92(m, 4H), 6.25(dd, 1H); MS(APCI)m/z(rel intensity)409.3(100). 95% yield. 220 CH₂(4-I)Ph mp 76–94° C.: ¹H NMR(CDCl₃): δ2.18(s, 3H), 2.46–2.36(m, 3H), 2.47(s, 3H), 2.78(dd, 1H), 2.90(dt, 1H), 3.09(d, 1H), 3.20(ddd, 1H), 3.56(d, 1H), 3.96(d, 1H), 4.91(s, 1H), 5.97(s, 1H), 6.57(dd, 1H), 6.85(ddd, 1H), 6.97–6.89(m, 4H), 7.60–7.56(m, 2H); MS(APCI)m/z(rel intensity)529.3(100). 87% yield. 221 CH₂(4-OiPr)Ph mp 92–98° C.: ¹H NMR(CDCl₃): δ1.32(d, 3H), 1.33(d, 3H), 2.14(s, 3H), 2.39–2.32(m, 2H), 2.42(dd, 1H), 2.48(s, 3H), 2.77(dd, 1H), 2.91(dt, 1H), 3.10(d, 1H), 3.18(dd, 1H), 3.62(d, 1H), 3.98(d, 1H), 4.49(qt, 1H), 4.89(s, 1H), 5.99(s, 1H), 6.56(d, 1H), 6.81–6.76(m, 2H), 6.84(dd, 1H), 6.93(d, 2H), 7.04(d, 2H); MS(APCI)m/z(rel intensity)461.5(100). 96% yield.

By a method similar to Example 58, using the appropriate starting materials, the following piperazine were prepared and isolated.

No: ArAlk Data 222 CH₂(4-I)Ph ¹H NMR(CDCl₃): δ2.52–2.60(m, 2H), 2.69(dd, 1H), 2.81–2.93(m, 2H), 2.99–3.10(m, 4H), 6.95(d, 2H), 7.63(d, 2H); MS(APCI)m/z(rel intensity)303(100).

Example 223 3-(S)-(4-(3-Methyl-but-2-enyloxy)-benzyl-piperazine-2,5-dione

To a suspension of 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (15 g, 68.2 mmol), cesium carbonate (111 g, 340 mmol), and tetrabutylammonium iodide (1.25 g, 3.4 mmol) in anhydrous DMF. (500 mL), add at once, at ambient temperature, 1-bromo-3-methyl-but-2-ene (51 g, 340 mmol). Stir 12 hours then add water (300 mL). Concentrate to dryness then add water (500 mL) and extract with a dichloromethane/isopropyl alcohol (3/1) mixture. Wash the organic phases with 10% aqueous potassium carbonate and water then dry over magnesium sulfate. Evaporate the solvent, then triturate the resulting solid with chloroform. Filter and dry to yield (14.3 g, 73%) of the title compound as a white solid: mp 217–220° C.: ¹H NMR (DMSO-d₆): δ 1.69 (s, 3H), 1.74 (s, 3H), 2.84–2.76 (m, 2H), 3.02 (dd, 1H), 3.36 (dd, 1), 4.01 (m, 1H), 4.48 (d, 2H), 5.41 (m, 1H), 6.84 (d, 2H), 7.05 (d, 2H), 7.86 (s, 1H), 8.12 (d, 1H).

By a method similar to Example 223, using the appropriate starting materials, the following compounds were prepared and isolated.

No: ArAlk Data 224 CH₂(4-OCH₂CH═CH₂)Ph mp 258° C.: ¹H NMR(DMSO-d₆): δ2.78(d, 1H), 2.81(dd, 1H), 3.03(dd, 1H), 3.35(dd, 1H), 4.01(m, 1H), 4.53(d, 2H), 5.24(dd, 1H), 5.38(dd, 1H), 6.07–5.96(m, 1H), 6.86(d, 2H), 7.06(d, 2H), 7.87(s, 1H), 8.11(d, 1H). 224a CH₂-(4-OCH₂C(═CH₂)CH₃Ph mp 248–249° C.: ¹H NMR(DMSO-d₆) δ1.75(s, 3H), 2.78(d, 1H), 2.81(dd, 1H), 3.03(dd, 1H), 3.35(dd, 1H), 4.01(m, 1H), 4.43(s, 2H), 4.94(s, 1H), 5.04(s, 1H), 6.86(d, 2H), 7.06(d, 2H), 7.87(s, 1H), 8.11(d, 1H).

By a method similar to Example 24, using the appropriate starting materials, the following piperazines were prepared and isolated were prepared and isolated as the (S) isomer except where noted below.

No: ArAlk Data 225 CH₂(4-O—CH₂CH═CH₂)Ph mp 89–90° C.: ¹H NMR(CDCl₃): δ2.45(dd, 1H), 2.48(dd, 1H), 2.63(dd, 1H), 2.82–2.67(m, 3H), 2.90(dd, 2H), 2.96(dd, 1H), 4.51(t, 1H), 4.52(t, 1H), 5.28(dq, 1H), 5.41(dq, 1H), 6.11–6.00(m, 1H), 6.86(d, 2H), 7.11(d, 2H); MS (APCI)m/z(rel intensity)233.3(100). 226 CH₂(thiophen-3-yl) mp 75–77° C.: ¹H NMR(CDCl₃): δ2.48(dd, 1H), 2.59(dd, 1H), 2.95–2.66(m, 6H), 2.98(dd, 1H), 6.95(dd, 1H), 7.02(m, 1H), 7.28(m, 1H); MS(APCI)m/z(rel intensity)183.2 (100). 227 CH₂(4-OiPr)Ph ¹H NMR(CDCl₃)δ1.31(s, 3H), 1.33(s, 3H), 2.45(dd, 1H), 2.48(dd, 1H), 2.63(dd, 1H), 2.82–2.67(m, 3H), 2.90(dd, 2H), 2.96(dd, 1H), 4.45(qt, 1H), 6.81(d, 2H), 7.15(d, 2H); MS(APCI)m/z(rel intensity)235.3(100). 228 CH₂(4-OPh)Ph ¹H NMR(CDCl₃)δ2.48(dd, 1H), 2.52(dd, 1H), 2.67(dd, 1H), 2.70–2.96(m, 5H), 2.98(dd, 1H), 6.95(d, 2H), 7.01(d, 2H), 7.10(t, 1H), 7.16(d, 2H), 7.32(t, 2H); MS(APCI)m/z (rel intensity)269(100). 229 CH₂(4-i-Pr)Ph ¹H NMR(CDCl₃)δ1.24(d, 6H), 2.47(dd, 1H), 2.50(dd, 1H), 2.63–2.92(m, 7H), 2.96(dd, 1H), 7.09–7.17(m, 4H); MS(APCI)m/z(rel intensity)219(100). 230 CH₂(3,5-DiCH₃)Ph ¹H NMR(CDCl₃)δ2.28(s, 6H), 2.43(dd, 1H), 2.49(dd, 1H), 2.62(dd, 1H), 2.66–2.99(m, 6H), 6.82(s, 2H), 6.86(s, 1H); MS(APCI)m/z(rel intensity)205(100). 231 CH₂(3,4-OCH₂O—)Ph mp 80–84° C.; ¹H NMR(CDCl₃)δ2.40(dd, 1H), 2.70(dd, 1H), 2.61(dd, 1H), 2.82–2.71(m, 3H), 2.99–2.87(m, 3H), 5.93(s, 2H), 6.76–6.62(m, 3H); MS(APCI)m/z(rel intensity)221.3(100). 232 CH₂(4-O—CH₂CH═C(CH₃)₂)Ph mp 43–47° C.: ¹H NMR(CDCl₃)δ1.77(s, 3H), 1.89(s, 3H), 2.45(dd, 1H), 2.48(dd, 1H), 2.63(dd, 1H), 2.82–2.67(m, 3H), 2.90(dd, 2H), 2.96(dd, 1H), 4.48(s, 2H), 5.49(ddd, 1H), 6.85(d, 2H), 7.10(d, 2H); MS(APCI)m/z(rel intensity)261.5(100). 233 CH₂(4-O—CH₂C(═CH₂)CH₃)Ph mp 73–75° C.: ¹H NMR(CDCl₃)δ1.83(s, 3H), 2.45(dd, 1H), 2.48(dd, 1H), 2.63(dd, 1H), 2.82–2.67(m, 3H), 2.90 (dd, 2H), 2.96(dd, 1H), 4.41(s, 2H), 4.98(s, 1H), 5.09(s, 1H), 6.85(d, 2H), 7.09(d, 2H); MS(APCI)m/z(rel intensity)247.4(100). 234 CH₂(3,4-DiO—CH₃)Ph ¹H NMR(CDCl₃)δ2.45(dd, 1H), 2.50(dd, 1H), 2.65(dd, 1H), 2.82–2.71(m, 3H), 2.96–2.87(m, 2H), 2.98(dd, 1H), 3.86(s, 3H), 3.87(s, 3H), 6.83–6.72(m, 3H); MS(APCI)m/z (rel intensity)237.3(100). 235 CH₂(2-OCH₂CH₃)Ph ¹H NMR(CDCl₃)δ1.43(t, 3H), 2.45–2.53(m, 2H), 2.71– 2.79(m, 3H), 2.86–2.95(m, 4H), 4.03(q, 2H), 6.82–6.87(m, 2H), 7.12–7.28(m, 2H); MS(APCI)m/z(rel intensity)221 (100). 235a CH₂(3-OPh)Ph ¹H NMR(CDCl₃)δ2.47(dd, 1H), 2.49(dd, 1H), 2.64(dd, 1H), 2.67–2.96(m, 6H), 6.86(d, 1H), 6.88(s, 1H), 6.93(d, 1H), 7.01(d, 2H), 7.10(t, 1H), 7.24(t, 1H), 7.33(t, 2H); MS (APCI)m/z(rel intensity)269(100). 235b CH₂(2,4-Di-OCH₃)Ph ¹H NMR(CDCl₃)δ2.43(dd, 1H), 2.47(dd, 1H), 2.66(dd, 1H), 2.69–2.96(m, 6H), 3.78(s, 3H), 3.79(s, 3H), 6.41(d, 1H), 6.44(s, 1H), 7.03(d, 1H); MS(APCI)m/z(rel intensity)237(100).

By a method similar to Example 59, using the appropriate starting materials, the following compounds were prepared and isolated as the (S) isomer except where noted below:

No: ArAlk Data 236 CH₂(3,5-DiCH₃)Ph ¹H NMR(CDCl₃)δ2.27(s, 3H), 2.29(s, 6H), 2.51(dd, 1H), 2.69(dd, 1H), 2.74(dd, 1H), 2.82(ddd, 1H), 2.93–3.02(m, 3H), 3.99(m, 1H), 4.12(m, 1H), 4.96(s, 1H), 6.23(s, 1H), 6.60(d, 1H), 6.85(s, 2H), 6.86(s, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.02(d, 1H); MS(APCI)m/z(rel intensity)417(100). 35% yield. 237 CH₂(4-O—CH₂C(═CH₂)CH₃)Ph mp 106–113° C.; ¹H NMR(CDCl₃)δ1.83(s, 3H), 2.26(s, 3H), 2.56(dd, 1H), 2.66(dd, 1H), 2.73(dd, 1H), 2.84(dd, 1H), 3.04–2.92(m, 3H), 4.00(d, 1H), 4.08(d, 1H), 4.41(s, 2H), 4.95(s, 1H), 4.99(m, 1H), 5.09(m, 1H), 6.20(d, 1H), 6.60(dd, 1H), 6.89–6.84(m, 3H), 6.96(dt, 1H), 7.02(dd, 1H), 7.15–7.01(m, 2H); MS(APCI)m/z(rel intensity)459.5 (100). 41% yield. 238 CH₂(2-OCH₂CH₃)Ph ¹H NMR(CDCl₃)δ1.42(t, 3H), 2.22(s, 3H), 2.62(dd, 1H), 2.68(dd, 1H), 2.83–2.90(m, 2H), 2.97(ddd, 1H), 3.02–3.11(m, 2H), 3.97(m, 1H), 4.02(q, 2H), 4.03(m, 1H), 4.99(s, 1H), 6.18(s, 1H), 6.59(d, 1H), 6.82–6.89(m, 3H), 6.95(t, 1H), 7.01(d, 1H), 7.16–7.21(m, 2H); MS(APCI)m/z(rel intensity)433(100). 50 mg of product. 239 CH₂(2-O-i-Pr)Ph ¹H NMR(CDCl₃)δ1.33(dd, 6H), 2.22(s, 3H), 2.55(m, 1H), 2.65(m, 1H), 2.81–3.20(m, 5H), 3.92(d, 1H), 4.07(d, 1H), 4.51(m, 1H), 4.91(s, 1H), 6.16(s, 1H), 6.58(d, 1H), 6.85(m, 3H), 6.95(t, 1H), 6.99(d, 1H), 7.15(d, 2H); MS(ESI) m/z(rel intensity)447(100). 1.0 g of product. 240 CH₂(pyridin-2-yl) mp 115–117° C.(decomp); ¹H NMR(CDCl₃)δ2.25(s, 3H), 2.90–2.96(m, 4H), 3.10–3.20(m, 2H), 3.40(m, 1H), 4.05(m, 2H), 5.09(bs, 1H), 6.22(s, 1H), 6.60(d, 1H), 6.85(t, 1H), 6.96(t, 1H), 6.99(d, 1H), 7.12–7.20(m, 2H), 7.60(t, 1H), 8.52(d, 1H); MS(es)m/z(rel intensity)390(100). 50 mg of product. 240a CH₂(3-OPh)Ph mp 97–103° C.; ¹H NMR(CDCl₃)δ2.26(s, 3H), 2.62(dd, 1H), 2.65(dd, 1H), 2.75(dd, 1H), 2.86(dd, 1H), 2.94(dd, 1H), 3.05–2.97(m, 2H), 3.99(d, 1H), 4.06(d, 1H), 4.94(s, 1H), 6.20(s, 1H), 6.59(dd, 1H), 6.90–6.84(m, 3H), 7.04– 6.93(m, 5H), 7.11(ddd, 1H), 7.27(t, 1H), 7.36–7.31(m, 2H); MS(APCI)m/z(rel intensity)481.5(100). 43% yield.

By a method similar to Example 90, using the appropriate starting materials, the following compounds were prepared and isolated as the free base and as the (S) isomer except where noted:

No: ArAlk Data 241 CH₂(4-O—CH₂CH═C(CH₃)₂)Ph mp 74–78° C.; ¹ H NMR(CDCl₃)δ1.75(s, 3H), 1.81(s, 3H), 2.13(s, 3H), 2.39–2.32(m, 2H), 2.42(dd, 1H), 2.48(s, 3H), 2.76(dd, 1H), 2.91(dt, 1H), 3.11(d, 1H), 3.18(dd, 1H), 3.61(d, 1H), 3.99(d, 1H), 4.47(d, 2H), 4.91(s, 1H), 5.50(m, 1H), 5.97(bs, 1H), 6.56(dd, 1H), 6.87–6.79(m, 3H), 6.95– 6.91(m, 2H), 7.05(d, 2H); MS(APCI)m/z(rel intensity) 487.5(100). 93% yield. 242 CH₂(3,4-OCH₂O—)Ph mp 105–108° C.; ¹H NMR(CDCl₃)δ2.18(d, 3H), 2.39–2.32 (m, 2H), 2.43(dd, 1H), 2.47(s, 3H), 2.78(dd, 1H), 2.90(dt, 1H), 3.08(d, 1H), 3.20(dd, 1H), 3.61(d, 1H), 3.97(d, 1H), 4.91(s, 1H), 5.92(dd, 2H), 6.02(bs, 1H), 6.57(dd, 1H), 6.60(dd, 1H), 6.72–6.66(m, 2H), 6.85(ddd, 1H), 6.96–6.92(m, 2H); MS(APCI)m/z(rel intensity)447.4(100). 90% yield. 243 CH₂(3,4-di-OCH₃)Ph mp 103–108° C.; ¹H NMR(CDCl₃)δ2.13(s, 3H), 2.39–2.32(m, 2H), 2.43(dd, 1H), 2.49(s, 3H), 2.76(dd, 1H), 2.91(dt, 1H), 3.15–3.08(m, 1H), 3.18(dd, 1H), 3.67(d, 1H), 3.83(s, 3H), 3.86(s, 3H), 4.00(d, 1H), 4.91(s, 1H), 5.96(bs, 1H), 6.57(dd, 1H), 6.65(d, 1H), 6.70(dd, 1H), 6.77(d, 1H), 6.85(ddd, 1H), 6.95–6.91(m, 2H); MS(APCI)m/z(rel intensity) 463.4(100). 90% yield. 244 CH₂(4-O—CH₂C(═CH₂)CH₃)Ph mp 93–100° C.; ¹H NMR(CDCl₃)δ1.83(s, 3H), 2.14(s, 3H), 2.44–2.32(m, 3H), 2.48(s, 3H), 2.76(dd, 1H), 2.91(dt, 1H), 3.11(d, 1H), 3.18(dd, 1H), 3.61(d, 1H), 3.98(d, 1H), 4.40(s, 2H), 4.90(s, 1H), 4.99(m, 1H), 5.09(m, 1H), 5.98 (bs, 1H), 6.56(dd, 1H), 6.87–6.79(m, 3H), 6.95–6.91(m, 2H), 7.05(d, 2H); MS(APCI)m/z(rel intensity)473.5(100). 94% yield. 245 CH₂(4-iPr—Ph) mp 94–99° C.; ¹H NMR(CDCl₃)δ1.23(d, 3H), 1.25(d, 3H), 2.16(s, 3H), 2.46–2.38(m, 3H), 2.49(s, 3H), 2.93–2.79(m, 3H), 3.12(d, 1H), 3.22(dd, 1H), 3.6(d, 1H), 3.92(d, 1H), 4.91(s, 1H), 6.07(bs, 1H), 6.84(ddd, 1H), 6.96–6.88(m, 2H), 7.16–6.04(m, 5H); MS(APCI)m/z(rel intensity)445.6 (100). 77% yield. 246 CH₂(3,5-DiCH₃)Ph mp 96–103° C.; ¹H NMR(CDCl₃)δ2.10(s, 3H), 2.25(s, 6H), 2.48–2.32(m, 3H), 2.49(s, 3H), 2.87(dd, 1H), 2.91(dt, 1H), 3.10–3.05(m, 1H), 3.26(dd, 1H), 3.62(d, 1H), 3.94(d, 1H), 5.00(m, 1H), 5.96(bs, 1H), 6.56(d, 1H), 6.74(d, 2H), 6.81(s, 1H), 6.83(dd, 1H), 6.94–6.90(m, 2H); MS(APCI) mz/(rel intensity)431.5(100). 82% yield. 247 CH₂(2-OCH₂CH₃)Ph mp 135–137° C.; ¹H NMR(CDCl₃)δ1.41(t, 3H), 2.10(s, 3H), 2.42(d, 3H), 2.53(s, 3H), 2.86–2.95(m, 2H), 3.20(m, 2H), 3.61(d, 1H), 4.02(m, 3H), 4.89(s, 1H), 5.96(s, 1H), 6.56(d, 1H), 6.84(m, 3H), 6.92(d, 2H), 7.08(d, 1H), 7.15 (t, 1H); MS(ESI)m/z(rel intensity)447(100). 278 mg of product. 248 CH₂(4-Ph)Ph ¹H NMR(CDCl₃)δ2.03(s, 3H), 2.42–2.53(m, 3H), 2.52(s, 3H), 2.87(m, 1H), 2.95(ddd, 1H), 3.21(m, 2H), 3.63(m, 1H), 3.96(m, 1H), 4.89(s, 1H), 6.01(s, 1H), 6.56(d, 1H), 6.84(m, 1H), 6.92(m, 2H), 7.25(d, 2H), 7.34(t, 1H), 7.43(t, 2H), 7.50(d, 2H), 7.58(d, 2H); MS(APCI)m/z(rel intensity)479(100). 421 mg of product. 249 CH₂(2-O—iPr)Ph mp 184–186° C.; ¹H NMR(CDCl₃)δ1.21(d, 3H), 1.35(d, 3H), 2.07(s, 3H), 2.41(m, 3H), 2.53(s, 3H), 2.83–2.96(m, 2H), 3.19(m, 2H)3.59(d, 1H), 4.00(d, 1H), 4.55(m, 1H), 4.87(s, 1H), 5.92(s, 1H), 6.55(d, 1H), 6.81(m, 3H), 6.92(d, 2H), 7.08(d, 1H), 7.13(t, 1H); MS(ESI)m/z(rel intensity)461(100). 378 mg of product.

Example 255 1-Acetyl-3-(pyridin-3-yl)methylene-piperazine-2,5-dione

Add DMF (60 mL) to a mixture of 1,4-diacetyl-piperazine-2,5-dione (5.94 g, 30 mmol) and 3-pyridinecarboxaldehyde (12.84 g, 120 mmol). Cool to 0° C. Add portionwise over 20 min a solution of potassium tert-butoxide (3.36 g, 30 mmol) in tert-butanol (60 mL) to this solution. Warm to room temperature and stir for 2 h. Pour the mixture into water (400 mL) and filter. Wash with water three times, then with hexanes to obtain the title compound as a yellow powder (4.0 g, 54%): ¹H NMR (DMSO-d₆) δ 2.51 (s, 3H), 4.37 (s, 2H), 6.95 (s, 1H), 7.43 (dd, 1H), 7.96 (d, 1H1), 8.50 (d, 1H), 8.73 (s, 1H), 10.64 (bs, 1H).

By the method of example 255, the following compounds were prepared and isolated:

No: R Data 256 2-pyridyl ¹H NMR(DMSO-d₆)δ2.49(s, 3H), 4.32(s, 2H), 6.85(s, 1H), 7.36(dd, 1H), 7.67(d, 1H), 7.90(t, 1H), 8.70(d, 1H), 12.43(bs, 1H). 78% yield, 36 g. 257 (3,5-Di-OCH₃)Ph ¹H NMR(CDCl₃)δ2.61(s, 3H), 3.73(s, 6H), 4.56(s, 2H), 6.43(s, 1H), 6.45(s, 2H), 7.06(s, 1H), 8.09(bs, 1H). 98% yield 17.8 g gave 26.8 g. 258 (3,5-Di-CH₃)Ph mp 172–174° C.: ¹H NMR(CDCl₃)δ2.30(s, 6H), 2.61(s, 3H), 4.46(s, 2H), 6.95(s, 2H), 6.98(s, 1H), 7.08(s, 1H), 7.99(bs, 1H). 64% yield, 17.8 g gave 15.8 g. 259 (2-OEt)Ph mp 142–145° C.: ¹H NMR(CDCl₃)δ1.48(t, 3H), 2.63(t, 3H), 4.17(q, 2H), 4.45(s, 2H), 6.96(d, 1H), 7.01(t, 1H), 7.11(s, 1H), 7.30(d, 1H), 7.34(t, 1H), 8.80(bs, 1H). 64% yield, from 17.8 g gave 16.5 g. 260 (4-OPh)Ph mp 165–167° C.: ¹H NMR(CDCl₃)δ2.62(s, 3H), 4.48(s, 2H), 7.01–7.03(m, 4H), 7.11(s, 1H), 7.15(t, 1H), 7.33–7.38(m, 4H), 7.97(bs, 1H). 92% yield, 23.8 g gave 37.0 g 261 (4-i-Pr)Ph mp 155–168° C.: ¹H NMR(CDCl₃)δ1.24(d, 6H), 2.62(s, 3H), 2.90(septet, 1H), 4.48(s, 2H), 7.13(s, 1H), 7.27–7.31(m, 4H), 7.91(bs, 1H). 83% yield, 23.8 g gave 32.7 g 262 (2-OiPr)Ph mp 187–192° C.; ¹H NMR(CDCl₃)δ1.41(d, 6H), 2.67(s, 3H), 4.47(s, 2H), 4.71(m, 1H), 7.00(m, 2H), 7.11(s, 1H), 7.31(m, 2H). 263 (2,4-Di-OCH₃)Ph ¹H NMR(DMSO-d₆)δ2.42(s, 3H), 3.75(s, 3H), 3.78(s, 3H), 4.26(s, 2H), 6.54(d, 1H), 6.55(s, 1H), 6.99(s, 1H), 7.49(d, 1H), 10.01(bs, 1H).

Example 266 (S)-1-Acetyl-3-(3-phenoxy-benzyl)-piperazine-2,5-dione

Add EtOH (60 mL) and DMF (15 mL) to the dehydrodiketopiperazine (15–50 g). Exchange the atmosphere to nitrogen with a Parr shaker. Add a catalytic amount of Pd/C (DeGaussa type from Aldrich, 50% water, 100 mg). Exchange the atmosphere three times with hydrogen to a pressure of 30 psi. During the reaction, the mixture will form a solution (except for the catalyst) and shake for an additional 30 minutes or until no more hydrogen uptake is observed. Filter the catalyst through celite, and concentrate to dryness to obtain the title compound as a white solid Separation of the S-isomers occurs via resolution of the piperazines. In all other examples, only the ethanol was removed and the crude product was used as is in a solution in DMF for treatment with hydrazine as in example 267. ¹H NMR (CDCl₃) δ 2.54 (s, 3H), 3.11 (dd, 1H), 3.18 (dd, 1H), 3.50 (d, 1H), 4.22 (d, 1H), 4.36 (m, 1H), 6.82 (s, 1H), 6.90–6.93 (m, 2H), 6.96 (d, 2H), 7.12 (t, 1H), 7.18 (bs, 1H), 7.27 (t, 1H), 7.34 (t, 2H).

Example 267 3-(3-Phenoxy-benzyl)-piperazine-2,5-dione

Add hydrazine hydrate (0.7 mL, 14.2 mmol) to a solution of 1-acetyl-3-(3-phenoxy-benzyl)-piperazine-2,5-dione (4.8 g, 14.2 mmol) in DMF (10 mL). Stir 2 h, dilute with water (50 mL) and stir an additional 30 minutes. Filter, wash with water, then cold methanol to obtain the title compound as a white powder (2.8 g, 67%): ¹H NMR (CDCl₃) δ 2.84 (dd, 1H), 2.96 (d, 1H), 3.05 (dd, 1H), 3.42 (d, 1H), 4.03 (m, 1H), 6.83–6.97 (m, 5H), 7.09 (t, 1H), 7.27 (t, 1H), 7.34 (t, 2H), 7.92 (bs, 1H), 8.12 (s, 1H).

By the method of example 266 and 267, the following compounds were prepared and isolated: Separation of the S-isomers occurs via resolution of the piperazines with the use of tartartic acid.

No: R Data 269 (3,5-Di-OCH₃)Ph mp 212–213° C.: ¹H NMR(DMSO-d₆) δ2.76(dd, 1H), 2.87(d, 1H), 2.93(dd, 1H), 3.34(d, 1H), 3.63(s, 6H), 3.99(m, 1H), 6.28(s, 2H), 6.32(s, 1H), 7.87(bs, 1H), 8.05(bs, 1H). 48% yield, 11.1 g from 26.8 g. 270 (2-OEt)Ph mp 180–181° C.: ¹H NMR(DMSO-d₆)δ1.30(t, 3H), 2.90(dd, 1H), 2.99(dd, 1H), 3.12(d, 1H), 3.35(d, 1H), 3.91(m, 1H), 3.93(q, 2H), 6.79(t, 1H), 6.88(d, 1H), 7.05(d, 1H), 7.18(t, 1H), 7.79(bs, 1H), 7.86(bs, 1H). 65% yield, 16.5 g gave 9.2 g. 271 (2-O-i-Pr)Ph mp 217–218° C.; ¹H NMR(DMSO-d₆)δ1.24(d, 6H), 2.6–3.4(m, 4H), 3.89(m, 1H), 4.52(m, 1H), 6.78(t, 1H), 6.88(d, 1H), 7.06(d, 1H), 7.16(d, 1H), 7.77(s, 1H), 7.88(s, 1H). 272 (4-i-Pr)Ph mp > 250° C.: ¹H NMR(DMSO-d₆)δ1.14(d, 6H), 2.71(d, 1H), 2.81(septet, 1H), 2.82(dd, 1H), 3.01(dd, 1H), 3.30(d, 1H), 4.00(m, 1H), 7.04(d, 2H), 7.10(d, 2H), 7.83(bs, 1H), 8.09(bs, 1H). 78% yield, 32.6 g gave 22.4 g. 273 (3,5-Di-CH₃)Ph mp 210–211° C.: ¹H NMR(DMSO-d₆)δ2.16(s, 6H), 2.77(dd, 1H), 2.79(d, 1H), 2.94(dd, 1H), 3.32(d, 1H), 3.98(m, 1H), 6.73(s, 2H), 6.84(s, 1H), 7.86(bs, 1H), 8.07(bs, 1H). 90% yield, 15.8 g gave 12.2 g. 274 (4-OPh)Ph mp 226–228° C.: ¹H NMR(DMSO-d₆) δ2.85(dd, 1H), 2.91(d, 1H), 3.02(dd, 1H), 3.40(d, 1H), 4.02(m, 1H), (6.93(d, 2H), 6.94(d, 1H), 7.09(t, 1H), 7.14(d, 1H), 7.35(t, 2H), 7.89(bs, 1H), 8.12(bs, 1H). 98% yield, 37.0 g gave 32.1 g. 275 (Pyrid-2-yl) ¹H NMR(DMSO-d₆)δ3.14(m, 2H), 3.41(d, 1H), 3.54(d, 2H), 4.17(m, 1H), 7.19–7.23(m, 2H), 7.68(t, 1H), 7.93(bs, 1H), 8.01(bs, 1H), 8.45(d, 1H). 276 (2,4-Di-OCH₃)Ph mp 221–223° C.: ¹H NMR(DMSO-d₆) δ2.77(dd, 1H), 2.90(dd, 1H), 3.14(d, 1H), 3.33(d, 1H), 3.79(m, 1H), 6.38(d, 1H), 6.45(s, 1H), 6.91(d, 1H), 7.75(bs, 1H), 7.83(bs, 1H).

Example 280 (S)-1,4-Dibenzyl-2-[2-(4-chloro-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (5.0 g, 17.10 mmol) and 9-borabicyclo[3.3.1]nonane (136.8 ml, 68.39 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-4-chloro-benzene (6.12 g, 25.65 mmol), triphenylphosphine (717.5 mg, 2.74 mmol), tetrakis(triphenylphosphine) palladium(0)(395.1 mg, 0.34 mmol), and 3N NaOH (14.0 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 4.76 g (69%) of the title compound: mp 87°–90°; mass spectrum (ion spray): m/z=405.4 (M+1); Analysis for C₂₆H₂₉ClN₂: calcd: C, 77.11; H, 7.22; N, 6.92; found: C, 76.93; H, 7.06; N, 7.01.

Example 281 (S)-1,4-Dibenzyl-2-[2-(3-chloro-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (5.0 g, 17.10 mmol) and 9-borabicyclo[3.3.1]nonane (136.8 ml, 68.39 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-3-chloro-benzene (6.12 g, 25.65 mmol), triphenylphosphine (717.5 mg, 2.74 mmol), tetrakis(triphenylphosphine)palladium(0)(395.1 mg, 0.34 mmol), and 3N NaOH (14.0 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 5.01 g (72%) of the title compound: mp 56°–60°; mass spectrum (ion spray): m/z=405.4 (M+1).

Example 282 (S)-1,4-Dibenzyl-2-[2-(2-chloro-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and 9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-2-chloro-benzene (7.34 g, 30.78 mmol), triphenylphosphine (861.0 mg, 3.28 mmol), tetrakis(triphenylphosphine)palladium(0)(474.1 mg, 0.41 mmol), and 3N NaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 2.59 g (31%) of the title compound: mass spectrum (ion spray): m/z=405.4 (M+1); Analysis for C₂₆H₂₉ClN₂: calcd: C, 77.11; H, 7.22; N, 6.92; found: C, 77.12; H, 7.13; N, 7.07.

Example 283 (S)-1,4-Dibenzyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and 9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-4-trifluoromethyl-benzene (8.37 g, 30.78 mmol), triphenylphosphine (861.0 mg, 3.28 mmol), tetrakis(triphenylphosphine)palladium(0 )(474.1 mg, 0.41 mmol), and 3N NaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 3.34 g (37%) of the title compound: mass spectrum (ion spray): mp 71°–75°; m/z=439.2 (M+1); Analysis for C₂₇H₂₉F₃N₂: calcd: C, 73.95; H, 6.67; N, 6.39; found: C, 74.15; H, 6.72; N, 6.52.

Example 284 (S)-1,4-Dibenzyl-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and 9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-2-trifluoromethyl-benzene (8.37 g, 30.78 mmol), triphenylphosphine (861.0 mg, 3.28 mmol), tetrakis(triphenylphosphine)palladium(0)(474.1 mg, 0.41 mmol), and 3N NaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum and dissolve the residue in ethyl acetate. Wash the organic layer with 1N NaOH then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue using ethyl acetate/hexanes (5:95) and reduce the appropriate fractions to residue. Stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 2.67 g (30%) of the title compound: mass spectrum (ion spray): mp 77°–82°; m/z=439.2 (M+1); Analysis for C₂₇H₂₉F₃N₂: calcd: C, 73.95; H, 6.67; N, 6.39; found: C, 74.11; H, 6.68; N, 6.50.

Example 285 (S)-2-[2-(4-Trifluoromethyl-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine (3.34 g, 7.62 mmol), ammonium formate (2.40 g, 38.09 mmol), 5% Pd/C (368.7 mg), and ethanol (100 ml). Stir and heat the mixture at reflux. After 3 hrs, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and then dissolve it in dichloromethane. Wash the organic with 1N NaOH and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue to give 1.83 g (93%) of the title compound as an off-white solid: mp 135°–141°; mass spectrum (ion spray): m/z=259.2 (M+1).

Example 286 (S)-2-[2-(2-Trifluoromethyl-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine (2.66 g, 6.06 mmol), ammonium formate (1.91 g, 30.31 mmol), 5% Pd/C (293.3 mg), and ethanol (100 ml). Stir and heat the mixture at reflux. After 3 hrs, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90:10) to give 1.46 g (93%) of the title compound as a white solid: mp 43°–47°; mass spectrum (ion spray): m/z=259.2 (M+1).

Example 287 (S)-2-[2-(2-chloro-phenyl)-ethyl]-piperazine

Dissolve (S)-1,4-dibenzyl-2-[2-(2-chloro-phenyl)-ethyl]-piperazine (2.59 g, 6.38 mmol) in dichloroethane (30 ml). Cool the solution to 0° and then add 1-chloroethyl chloroformate (2.74 g, 19.15 mmol) dropwise. Warm the solution to ambient temperature and then heat it at reflux for 15 hours. Remove the dichloroethane under vacuum and reflux the resulting residue in methanol for 1 hour. Remove the methanol under vacuum and dissolve the resulting precipitate in 1N NaOH. Extract the aqueous layer with dichloromethane and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90:10) to give 482.4 mg (34%) of the title compound: mass spectrum (ion spray): m/z=225.3 (M+1).

Example 288 (S)-2-[2-(4-chloro-phenyl)-ethyl]-piperazine

Dissolve (S)-1,4-dibenzyl-2-[2-(4-chloro-phenyl)-ethyl]-piperazine (4.74 g, 11.71 mmol) in dichloroethane (80 ml). Cool the solution to 0° and then add 1-chloroethyl chloroformate (7.95 g, 55.61 mmol) dropwise. Warm the solution to ambient temperature and then heat it at reflux for 15 hours. Remove the dichloroethane under vacuum and reflux the resulting residue in methanol for 1 hour. Remove the methanol under vacuum and dissolve the resulting precipitate in 1N NaOH. Extract the aqueous layer with dichloromethane and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90: 10) to give 459.0 mg (18%) of the title compound: mp 140°–144°; mass spectrum (ion spray): m/z=225.3 (M+1).

Example 289 (S)-2-[2-(3-chloro-phenyl)-ethyl]-piperazine

Dissolve (S)-1,4-dibenzyl-2-[2-(3-chloro-phenyl)-ethyl]-piperazine (4.48 g, 11.07 mmol) in dichloroethane (40 ml). Cool the solution to 0° and then add 1-chloroethyl chloroformate (4.75 g, 33.21 mmol) dropwise. Warm the solution to ambient temperature and then heat it at reflux for 42 hours. Remove the dichloroethane under vacuum and reflux the resulting residue in methanol (100 ml) for 1 hour. Remove the methanol under vacuum and dissolve the resulting precipitate in 1N NaOH. Extract the aqueous layer with dichloromethane and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90:10) to give 407.6 mg (16%) of the title compound: mp 93°–97°; mass spectrum (ion spray): m/z=225.3 (M+1).

Example 290 1,4-Dibenzyl-2-[2-(2,5-difluoro-phenyl)-ethyl]-piperazine

Prepared in a similar fashion to Example 284, Yield 23%, mass spectrum (m/e): 407.3 (M+1)

Example 291 2-[2-(2,5-Difluoro-phenyl)-ethyl]-piperazine

Dissolve1,4-dibenzyl-2-[2-(2,5-difluoro-phenyl)-ethyl]-piperazine (2.7 g, 6.6 mmol) in methanol (25 ml) and add 10% palladium on carbon (wet, 1.0 g). Carry out the hydrogenation with a hydrogen balloon at room temperature for 16 hours. Filter the reaction mixture, concentrate the filtrate under reduced pressure to give 2-[2-(2,5-difluoro-phenyl)-ethyl]-piperazine as an oil (1.5 g, 100%). mass spectrum (m/e): 227.0 (M+1).

Example 292 1,4-Dibenzyl-2-[2-(3-trifluoromethyl-phenyl)-ethyl]-piperazine

Prepared in a similar fashion to Example 284: Yield 73%, mass spectrum (m/e): 439.3 (M+1)

Example 293 2-[2-(3-Trifluoromethyl-phenyl)-ethyl]-piperazine

Prepared in a similar fashion to Example 286. Yield 100%, mass spectrum (m/e): 259.1 (M+1).

Example 373 2-Methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-thione

Suspend 2-methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-one (1.2 g, 4.8 mmol) in dry toluene and add Lawesson's reagent ( 1.1 g, 2.7 mmol) under nitrogen. Heat the reaction mixture under reflux for one hour and cool overnight. Precipate the desired material and collect by filtration, air-dry for several minutes to give 529 mg of yellow solid which can be used in the next step without further purification. Mass Spectrum (FIA) 265 (M+1); ¹H NMR (300 MHz, CDCl₃): 6.98 (s, 1H), 6.75 (t, 1H), 6.6 (t, 1H), 6.43 (d, 1H), 3.29 (s, 1H), 2.21 (s, 3H)

Example 374 2-Amino-5-tert-butyl-thiophene-3-carbonitrile

Add a solution of 3,3-dimethyl-butyraldehyde (20 g, 200 mmol) in EtOH (40 mL) dropwise a mixture of sulfur (6.4 g, 200 mmol), malononitrile (13.2 g, 200 mmol) and triethylamine (14.3 mL, 100 mmol) in EtOH (400 mL) at 0° C. Stir the mixture at room temperature for 20 minutes after the addition is complete, then reflux for 2 hours. Cool, concentrate to a paste. Add diethyl ether (200 mL) and 2N HCl (200 mL). Wash the organic layer again with 2N HCl, dry (Na₂SO₄), and concentrate. Purify the residue via column chromatography eluting with methylene chloride to afford the title compound as tan crystals (16.9 g, 47%): ¹H NMR (CDCl₃) δ 1.27 (s, 9H), 4.60 (bs, 2H), 6.36 (s, 1H).

Example 375 2-Amino-5-iso-propyl-thiophene-3-carbonitrile

Substitute isovaleraldehyde for 3,3-dimethyl-butyraldehyde and use the method of Example 374 to obtain the title compound as a brown solid: ¹H NMR (CDCl₃) δ1.24 (d, 6H), 2.93 (septet, 1H), 6.37 (s, 1H).

Example 376 2-Amino-5-cyclopentyl-thiophene-3-carbonitrile

Substitute 2-cyclopentylacetaldehyde for 3,3-dimethyl-butyraldehyde and substitute DMF for EtOH and use the method of Example 374 to obtain the title compound (16.1 g, 57%) as a yellow solid: ¹H NMR (CDCl₃) δ 1.48–1.58 (m, 2H), 1.61–1.69 (m, 2H), 1.72–1.78 (m, 2H), 1.98–2.07 (m, 2H), 3.01 (m, 1H), 4.58 (bs, 2H), 6.38 (s, 1H).

Example 378 5-tert-Butyl-2-(2-nitro-phenylamino)-thiophene-3-carbonitrile

Add a solution of 2-amino-5-tert-butyl-thiophene-3-carbonitrile (16.9 g, 94 mmol) in THF (50 mL) to a mixture of washed NaH (from 6.76 g of 60% mineral oil dispersion) in THF (200 mL) in a water bath at room temperature. Stir 15 minutes, then add a solution of 2-fluoro-nitrobenzene (13.2 g, 94 mmol) in THF (50 mL) dropwise. Stir overnight. Pour the purple reaction mixture unto 6 N HCl (400 mL). Extract the mixture with diethyl ether (400 mL). Wash the ether layer with 2 N HCl (400 mL), brine (250 mL), dry (Na₂SO₄), and concentrate to afford a mixture of crystals in a dark oily residue. Triturate the crystals with hexanes and filter to afford the title compound as a red powder (21.2 g, 75%) mp 85–90° C.: ¹H NMR (CDCl₃) δ 1.39 (s, 9H), 6.81 (s, 1H), 6.97 (t, 1H), 7.23 (d, 1H), 7.53 (t, 1H), 8.25 (d, 1H), 9.66 (bs, 1H).

By the method of example 378, the following compounds were prepared and isolated as the free base:

No: R¹ Data 379 i-Pr ¹H NMR(CDCl₃)δ1.35(d, 6H), 3.13(septet, 1H), 6.80(s, 1H), 6.96(t, 1H), 7.22(d, 1H), 7.54(t, 1H), 8.24(d, 1H), 9.65(s, 1H). 380 c-Pentyl ¹H NMR(CDCl₃)δ1.56–1.84(m, 6H), 2.11–2.19(m, 2H), 3.18(pentet, 1H), 6.80(s, 1H), 6.96(t, 1H), 7.21(d, 1H), 7.53(t, 1H), 8.25(d, 1H), 9.64(s, 1H).

Example 381 2-tert-Butyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride

Add 5-tert-butyl-2-(2-nitro-phenylamino)-thiophene-3-carbonitrile (21.2 g, 70 mmol) to a solution of tin(II)chloride dihydrate (46.1 g, 209 mmol) in conc. HCl (200 mL) and ethanol (600 mL). Reflux the mixture for 2 hours. Concentrate the solution to 200 mL and add to water (1 L). Filter and wash with water then hexanes to obtain the title compound as an orange powder (19.4 g): ¹H NMR (DMSO-d₆) δ 1.27 (s, 9H), 6.86 (d, 1H), 6.89 (s, 1H), 6.95 (d, 1H), 7.03 (t, 1H), 7.11 (t, 1H), 8.69 (s, 1H) 9.11 (s, 1), 9.52 (s, 1H), 10.88 (s, 1H); MS (APCI) m/z (rel intensity) 272 (100).

By the method of example 381, the following compounds were prepared and isolated as the free base:

No. R Data 382 i-Pr ¹H NMR(DMSO-d₆)δ1.16(d, 6H), 2.88(septet, 1H), 6.82(s, 1H), 6.83(d, 1H), 6.91(d, 1H), 6.99(t, 1H), 7.07(t, 1H), 8.71(s, 1H), 9.09(s, 1H), 9.54(s, 1H), 10.94(s, 1H). 383 c-Pentyl ¹H NMR(DMSO-d₆)δ1.42–1.70(m, 6H), 1.92–2.00(m, 2H), 2.99(pentet, 1H), 6.81(s, 1H), 6.82(d, 1H), 6.91(d, 1H), 6.99(t, 1H), 7.07(t, 1H), 8.63(bs, 1H), 9.05(bs, 1H), 9.50(bs, 1H), 10.79(bs, 1H).

Example 384 2-tert-Butyl-10-(4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

By a method similar to Example 59, using 2-tert-butyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.00 g, 3.26 mmol) and N-methyl-piperazine (1.9 g, 19 mmol) to obtain the title compound (904 mg, 78%) as a yellow powder: mp 125–130° C. (dec): ¹H NMR (CDCl₃) δ 1.29 (s, 9H), 2.35 (s, 3H), 2.50 (m, 4H), 3.53 (m, 4H), 4.96 (s, 1H), 6.33 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.96 (t, 1H), 7.02 (d, 1).

By a method similar to Example 59, the following compounds were prepared and isolated as the free base:

No: R² Data 385 i-Pr ¹H NMR(CDCl₃)δ1.23(d, 6H), 2.34(s, 3H), 2.50(m, 4H), 2.95(septet, 1H), 3.53(m, 4H), 5.00(s, 1H), 6.32(s, 1H), 6.60(d, 1H), 6.87(t, 1H), 6.97(t, 1H), 7.02(d, 1H); MS(APCI)m/z(rel intensity)581(100), 341(80). 386 c-Pentyl ¹H NMR(CDCl₃)δ1.48–1.79(m, 6H), 2.02(m, 2H), 2.35(s, 3H), 2.50(m, 4H), 3.04(pentet, 1H), 3.53(m, 4H), 4.95(s, 1H), 6.33(s, 1H), 6.60(d, 1H), 6.87(t, 1H), 6.97(t, 1H), 7.03(d, 1H); MS(APCI)m/z(rel intensity)367 (100).

Example 387 10-((S)-3-[2-(3-Chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (829.8 mg, 3.12 mmol), (S)-2-[2-(3-chloro-phenyl)-ethyl]-piperazine (1.40 g, 6.24 mmol), N,N-diisopropylethylamine (403.6 mg, 3.12 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 673.9 mg (50%) of the title compound as a brown foam: mp 68–74°, dec; mass spectrum (ES+): m/e=437.31.

Example 388 10-((S)-3-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (642.0 mg, 2.42 mmol), (S)-2-[2-(4-chloro-phenyl)-ethyl]-piperazine (1.09 g, 4.83 mmol), N,N-diisopropylethylamine (312.2 mg, 2.42 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 501.6 mg (47%) of the title compound as a brown foam: mp 91°, dec; mass spectrum (ion spray): m/z=437.3.

Example 389 10-((S)-3-[2-(2-Chloro-phenyl)-ethyl]-piperazin-l -yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (607.1 mg, 2.28 mmol), (S)-2-[2-(2-chloro-phenyl)-ethyl]-piperazine (1.03 g, 4.57 mmol), N,N-diisopropylethylamine (295.3 mg, 2.28 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 64 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 482.4 mg (48%) of the title compound as a brown foam: mp 72°, dec; mass spectrum (ion spray): m/z=437.3.

Example 390 10-((S)-3-[2-(4-Chloro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 10-((S)-3-[2-(4-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (430.9 mg, 0.99 mmol), formaldehyde (88.0 μL, 1.08 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (313.5 mg, 1.48 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 365.2 mg (82%) of the title compound as a brown foam: mp 79°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).

Example 391 10-((S)-3-[2-(3-Chloro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 10-((S)-3-[2-(3-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (608.3 mg, 1.53 mmol), formaldehyde (124.3 μL, 1.53 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (442.5 mg, 2.09 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 502.3 mg (80%) of the title compound as a brown foam: mp 69°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).

Example 392 10-((S)-3-[2-(2-Chloro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 10-((S)-3-[2-(2-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (398.3 mg, 0.91 mmol), formaldehyde (81.4 μL, 1.00 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (289.7 mg, 1.37 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 341.6 mg (83%) of the title compound as a brown foam: mp 72°, dec; mass spectrum (ion spray): m/z=451.1 (M+1).

Example 393 10-((S)-3-[2-(4-Trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (514.5 mg, 1.94 mmol), (S)-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87 mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 380.3 mg (42%) of the title compound as a brown foam: mp 78°, dec; mass spectrum (ion spray): m/z=471.1.

Example 394 10-((S)-3-[2-(2-Trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (514.5 mg, 1.94 mmol), (S)-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87 mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 497.4 mg (55%) of the title compound as a brown foam: mp 73°, dec; mass spectrum (ion spray): m/z=471.1.

Example 395 10-((S)-3-[2-(3-Trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (514.5 mg, 1.94 mmol), (S)-2-[2-(3-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87 mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 64 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 370.6 mg (41%) of the title compound as a brown foam: mp 69°, dec; mass spectrum (ion spray): m/z=471.1.

Example 396 10-((S)-3-[2-(4-Trifluoromethyl-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 10-((S)-3-[2-(4-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (325.3 mg, 0.69 mmol), formaldehyde (61.7 μL, 0.76 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (219.8 mg, 1.04 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 298.1 mg (89%) of the title compound as a tan foam: mp 72°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).

Example 397 10-((S)-3-[2-(2-Trifluoromethyl-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 10-((S)-3-[2-(2-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (365.7 mg, 0.78 mmol), formaldehyde (69.4 μL, 0.85 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (247.0 mg, 1.17 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 304.3 mg (81%) of the title compound as a tan foam: mp 68°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).

Example 398 10-C(S)-3-[2-(3-Trifluoromethyl-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 10-((S)-3-[2-(3-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (287.3 mg, 0.61 mmol), formaldehyde (54.5 μL, 0.67 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (194.1 mg, 0.92 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 228.0 mg (77%) of the title compound as a tan foam: mp 62°, dec; mass spectrum (ion spray): m/z=485.3 (N+1).

Example 399 10-((S)-3-[2-(2,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (351.6 mg, 1.32 mmol), (S)-2-[2-(2,4-difluoro-phenyl)-ethyl]-piperazine (600.0 mg, 2.65 mmol), N,N-diisopropylethylamine (171.0 mg, 1.32 mmol), DMSO (0.6 ml), and toluene (2.4 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 91.8 mg (16%) of the title compound as a brown foam: mp 69°, dec; mass spectrum (ion spray): m/z=439.0.

Example 400 10-((S)-3-[2-(2,4-Difluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 10-((S)-3-[2-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (57.3 mg, 0.61 mmol), formaldehyde (11.7 μL, 0.14 mmol, 37% in water), and 1,2-dichloroethane (5.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (41.5 mg, 0.20 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue to give 54.4 mg (92%) of the title compound: mass spectrum (ion spray): m/z=452.9 (M+1).

Example 401 6-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Suspend 2-methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-thione (370 mg, 1.4 mmol) in dichloromethane (30 ml), stir under nitrogen and cool in an ice/water bath. Addmethyl trifluoromethanesulfonate (400 μl), and stir the reaction mixture overnight. Concentrate the reaction mixture under reduced pressure, take up in pyridine (10 ml) and add (S-2[2′-(3-fluorophenyl)-ethyl]-piperazine) (300 mg, 1.4 mmol). Stir the reaction mixture under nitrogen and heat at 90° C. overnight. Concentrate the reaction mixture under reduced pressure and purify by flash column chromatography on silica gel (eluent dichloromethane/methanol) to give the desired as a light green oil 575 mg: mass Spectrum (FIA) 439 (M+1); NMR (¹H, 300 MHz, CDCl₃): 7.2 (m, 1H), 7.0 (m, 1H), 6.93 (m, 1H), 6.85 (m, 2H), 6.68 (m, 1H), 6.49 (m, 1H), 6.22 (s, 1H), 5.95 broad, 1H), 4.12 (m, 1H), 4.0 (m, 1H), 3.28 (m, 2H), 3.05 (m, 3H), 2.69 (m, 2H), 2.29 (s, 3H), 1.88 (m, 2H).

Example: 402 6-Fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using 2-methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-thione and (5–2[2′-(4-methoxyphenyl)-ethyl]-piperazine): mass Spectrum (FIA) 451 (M+1); NMR (¹H, 300 MHz, CDCl₃): 7.10 (d, 2H), 6.94 (m, 1H), 6.82 (d, 2H), 6.68 (m, 1H), 6.38 (m, 1H), 6.28 (s, 1H), 5.07 broad, 1H), 4.02 (m, 1H), 3.87 (m, 1H), 3.78 (s, 3H), 3.12 (m, 1H), 2.8–2.9 (m, 2H), 2.7 (m, 1H), 2.55 (m, 1H), 2.29 (s, 3H), 1.9 (m, 2H), 1.7 (m, 2H).

Example 403 7-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using 2-methyl-4,9-dihydro-3-thia-7-fluoro-4,9-diazabenzo[f]azulene-10-thione and (S-2[2′-(3-fluorophenyl)-ethyl]-piperazine): mass Spectrum (FIA) 439 (M+1); NMR (¹H, 300 MHz, CDCl₃): 7.22 (m, 1H), 6.95 (m, 1H), 6.88 (m, 2H), 6.72 (m, 1H), 6.5–6.7 (m, 2H), 6.24 (s, 1H), 5.05 (broad, 1H), 4.22 (m, 1H), 4.03 (m, 1H), 3.30 (m, 2H), 3.10 (m, 3H), 2.69 (m, 2H), 2.32 (s, 3H), 1.93 (m, 2H).

Example 404 7-Fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using 2-methyl-4,9-dihydro-3-thia-7-fluoro-4,9-diazabenzo[f]azulene-10-thione and (S-2[2′-(4-methoxyphenyl)-ethyl]-piperazine): mass Spectrum (FIA) 451 (M+1); NMR (¹H, 300 MHz, CDCl₃): 7.05 (d, 2H), 6.79 (d, 2H), 6.70 (m, 1H), 6.52–6.68 (m, 2H), 6.22 (s, 1H), 5.13 (broad, 1H), 4.22 (m, 1H), 4.02 (m, 1H), 3.74 (s, 3H), 3.3–3.4 (m, 2H), 3.03–3.27 (m, 3H), 2.63 (m, 2H), 2.33 (s, 3H), 1.9–2.1 (m, 2H).

Example 405 6-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene hydrochloride

Dissolve 6-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (695 mg, 1.58 mmol) in 1,2-dichloroethane (30 ml) and stir at room temperature. Add 37% Aqueous formaldehyde solution (1 ml) followed by sodium triacetoxyborohydride (0.35 g, 1.65 mmol). Stir the reaction mixture at room temperature overnight. Add saturated aqueous sodium and collect the organic phase, dry and concentrate to 1.2 g dark oil. Dissolve in methanol (20 ml), add 2N hydrochloric acid (5 ml) and stir the mixture at room temperature for 2 hours. Concentrate the reaction mixture and partitions between dichloromethane and 2N sodium hydroxide solution. Collect the organic phase, dry and concentrate to a dark oil. Purify the material by flash column chromatography on florisil (eluent dichloromethane/methanol) to give 0.3 g yellow oil. Dissolve this material in ethanol (20 ml), add 2N hydrochloric acid (2 ml) and concentrate the mixture and dry under high vacuum to give the desired title compound as an orange solid 312 mg: mass Spectrum (FIA) 389 (M+1); mp: 191–193° C.

Example: 406 6-Fluoro-10-{3-[2-(4-methoxy-phenyl-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene hydrochloride

Similarly prepared by using Example 405, using 6-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene. Mass Spectrum (FIA) 465 (M+1); mp: 191–193° C.

Example 407 7-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene hydrochloride

Similarly prepared by using Example 405, using 7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene. Mass Spectrum (FIA) 389 (M+1); mp: 178–180° C.

Example 408 7-Fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-4,9diaza-benzo[f]azulene

Similarly prepared by using Example 405, using 7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene. Mass Spectrum (FIA) 465 (M+1); mp: 180–182° C.

Example 410 2-Ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione

By using a method similar to Example 373, using 2-ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulen-10-one gives the title compound: Mass spectrum M=278.

Example 411 2-Ethyl-7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using 2-ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione to give the title compound: Mass spectrum M+H=453 for free base.

Example 412 2-Ethyl-7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene hydrochloride

Similarly prepared using Example 405, using 2-ethyl-7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene. Mass spectrum M+H=467 for free base. ¹H NMR (d6-DMSO); 11.73 (bs, 1H), 9.15 (bs, 1H), 7.35 (m, 1H), 7.05 (m, 6H), 6.66 (bs, 1H), 3.66 (m, 8H), 2.87 (m, 3H), 2.68 (m, 3H), 2.33 (m, 1H), 1.91 (m, 1H), 1.18 (m, 3H).

Example 413 2-Ethyl-7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using 2-ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione to give the title compound: Mass spectrum M+H=465 for free base.

Example 414 2-Ethyl-7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 405, using 2-ethyl-7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene: Mass Spectrum; M+H=479 for free base, ¹H NMR (d6-DMSO); 11.62 (bs, 1H), 9.19 (bs, 1H), 7.11 (bs, 3H), 6.99 (bs, 1H), 6.86 (m, 4H), 6.69 (bs, 1H), 3.73 (s, 3H), 3.63 (bs, 1H), 3.41 (bs, 2H), 3.38 (q, 2H, J=7.2 Hz), 3.17 (s, 1H), 2.85 (m, 5H), 2.71 (m, 4H), 2.27 (bs), 1.91 (bs), 1.19 (t, 3H J 7.3 Hz).

Example 415 (S)-1,4-Dibenzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine dihydrochloride

Combine 9-borabicyclo[3.3.1]nonane (119 mL, 59.5 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine (4.35 g, 14,9 mmol) and stir at ambient temperature. After 18 h, add triphenylphosphine (1.25 g, 4.76 mmol), tetrakis(triphenylphosphine)palladium(0) (688 mg, 0.60 mmol), THF (5 mL) and 1-iodonaphthalene (3.26 mL, 22.3 mmol). Add 3M NaOH (12.2 mL, 36.6 mmol) slowly, gas evolution occurs. Heat at reflux. After 24 h, cool to ambient temperature and concentrate under reduced pressure. Add 2N NaOH (200 mL), and stir 1 h. Extract with diethyl ether. Extract the diethyl ether solution with 1N H₂SO₄ and discard the diethyl ether. A white residue forms.

Add 5N NaOH to the 1N H₂SO₄ extracts until pH is 12–14. Extract with diethyl ether. Wash the diethyl ether extracts with brine, dry over sodium sulfate, filter and concentrate under reduced pressure to give 900 mg of crude product.

Dissolve the white residue in methanol and methylene chloride, dry over sodium sulfate, filter and concentrate under reduced pressure to give a tan foam. Slurry the foam in 5N HCl (50 mL), add methanol (50 mL) to give a homogeneous solution. Filter the white precipitate that forms to give 4.46 g (61%) of (S)-1,4-di-benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine dihydrochloride: mp 211–215° C. dec; mass spectrum (ion spray): m/z=421 (M+1). Analysis calculated for C₃₀H₃₄Cl₂N₂: C, 73.01; H, 6.94; N, 5.68; Cl, 14.37. Found: C, 72.98; H, 7.27; N, 5.59; Cl, 14.06.

Example 418, Example 419, Example 420 (S)-1-Benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine (S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine (S)-1-benzyl-2-(2-nalphthalen-1-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine (3.33 g, 7.92 mmol) in ethanol (100 mL). Add ammonium formate (2.99 g, 47.5 mmol) and palladium (666 mg, 5 wt. % on carbon) and heat to reflux. After 6 h 30 min, filter the palladium on carbon and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%–10%) and 7N ammonia in methanol-methylene chloride (20%) as the eluent to give 716 mg (38%) of (S)-2-(2-naphthalen-1-yl-ethyl)-piperazine, 1.1 g of (S)-1-benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine, and 290 mg of (S)-1-benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine.

(S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine: mass spectrum (ion spray): m/z=241 (M+1). ¹H NMR (DMSO-d₆, D₂O): δ 8.07 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.58–7.46 (m, 2H), 7.41 (dd, 1H), 7.36 (br d, 1H), 3.19–2.94 (m, 2H), 2.89–2.46 (m, 6H), 2.25 (dd, 1H), 1.60 (dd, 2H).

(S)-1-Benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine: mass spectrum (ion spray): m/z=331 (M+1). ¹H NMR (DMSO-d₆, D₂O): δ 8.03 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.57–7.47 (m, 2H), 7.44–7.18 (m, 7H), 3.90 (d, 1H), 3.23 (d, 1H), 3.17–2.90 (m, 3H), 2.78–2.39 (m, 5H), 2.14–2.04 (m, 1H), 1.99–1.89 (m, 2H).

(S)-1-Benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine: mass spectrum (ion spray): m/z=331 (M+1). ¹H NMR (DMSO-d₆): δ 8.06 (d, 1H), 7.90 (d, 1H), 7.74 (d, 1H), 7.56–7.45 (m, 2H), 7.40 (dd, 1H), 7.35–7.19 (m, 6H1), 3.42 (dd, 2H), 3.20–3.08 (m, 1H), 3.05–2.91 (m, 1H), 2.87–2.79 (m, 1H), 2.77–2.55 (m, 4H), 1.98–1.87 (m, 1H), 1.74–1.56 (m, 3H).

Example 421 (S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine

Dissolve (S)-1-benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine (1.07 g, 3.03 mmol) in ethanol (10 mL). Add ammonium formate (1.2 g, 19.0 mmol) and palladium hydroxide (200 mg, 20 wt. % on carbon) and heat to reflux. After 7 h, filter the palladium hydroxide and concentrate the filtrate. Combine with Example 422 and purify.

Example 422 (S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine

Dissolve (S)-1-benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine (280 mg, 0.85 mmol) in ethanol (5 mL). Add ammonium formate (320 mg, 5.1 mmol) and palladium hydroxide (60 mg, 20 wt. % on carbon) and heat to reflux. After 5.5 h, filter the palladium hydroxide and concentrate the filtrate. Combine with Example 421 and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (5%) and 7N ammonia in methanol-methylene chloride (20%) as the eluent to give 750 mg (81%) of the title compound: mass spectrum (ion spray): m/z=241 (M+1). ¹H NMR (DMSO-d₆): 8.08 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.59–7.32 (m, 4H), 3.53 (br s, 2H), 3.22–3.09 (m, 1H), 3.08–2.98 (m, 1H), 2.98–2.73 (m, 3H), 2.71–2.53 (m, 3H), 2.31 (dd, 1H), 1.71–1.57 (m, 2H).

Example 423 (S)-2-Methyl-10-[3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-naphthalen-1-yl-ethyl)-piperazine (686 mg, 2.85 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (654 mg, 2.85 mmol), toluene (5.7 mL), DMSO (1.4 mL) and glacial acetic acid (0.5 mL). Add N-ethyldiisopropylamine (2.0 mL). Heat at 105° C. After 48 h, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0.5%–5%) as the eluent to give 183 mg. Purify again by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–2%) as the eluent to give 60 mg (5%) of the title compound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1). Analysis calculated for C₂₈H₂₈N₄S.0.2H₂O: C, 73.71; H, 6.27; N, 12.28. Found: C, 73.37; H, 6.19; N, 12.00.

Example 424 (S)-2-Methyl-10-[3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-naphthalen-1-yl-ethyl)-piperazine (720 mg, 3.0 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (686 mg, 3.0 mmol), toluene (6 mL), DMSO (1.5 mL) and glacial acetic acid (1 drop). Heat at 105° C. After 48 h, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%–3%) as the eluent to give 290 mg (21%)of the title compound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1).

Example 425 (S)-2-Methyl-10-[4-methyl-3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Add formaldehyde (56 μL, 0.70 mmol, 37% in water) to a solution of (S)-2-methyl-10-[3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (290 mg, 0.64 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (204 mg, 0.96 mmol) and stir 30 min at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–2%) as the eluent to give 290 mg (97%) of the title compound: mass spectrum (ion spray): m/z=467 (M+1), 465 (M−1). HR-MS calculated for C₂₉H₃₁N₄S: 467.2269. Found 467.2278. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.

Example 426 (S)-1,4-Dibenzyl-2-(2-naphthalen-2-yl-ethyl)-piperazine dihydrochloride

Combine 9-borabicyclo[3.3.1]nonane (163.6 mL, 81.8 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine (5.98 g, 20.4 mmol) and stir at ambient temperature. After 24 h, add triphenylphosphine (1.72 g, 6.54 mmol), tetrakis(triphenylphosphine)palladium(0) (945 mg, 0.82 mmol) and 2-bromonaphthalene (6.35 g, 30.7 mmol). Add 3M NaOH (16.8 mL, 50.4 mmol) slowly, gas evolution occurs. Heat at reflux. After 24 h, cool to ambient temperature and concentrate under reduced pressure. Add 2.5N NaOH (200 mL), and stir 30 min. Extract with diethyl ether. Concentrate the diethyl ether extracts and dissolve the residue in 5N HCl (200 mL). Stir 30 min at ambient temperature. Extract with diethyl ether. Filter the precipitate that forms during the extraction. Slurry the precipitate in methanol, make basic with 5N NaOH, extract with diethyl ether, dry over sodium sulfate, filter and concentrate. Crystallize the residue from ethanol to give 5.9 g (69%) of the title compound: mp 85–8° C.; mass spectrum (ion spray): m/z=421 (M+1).

Example 427 (S)-2-(2-Naphthalen-2-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-naphthalen-2-yl-ethyl)-piperazine (6.53 g, 15.5 mmol) in ethanol (80 mL). Add ammonium formate (5.9 g, 93.6 mmol) and palladium hydroxide (1.5 g, 20 wt. % on carbon) and heat to reflux. After 8.5 h, cool and stir at ambient temperature 18 h. Filter the palladium hydroxide and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%–10%) as the eluent to give 2.86 g (77%) of the title compound: mp 151–4° C.; mass spectrum (ion spray): m/z=241 (M+1).

Example 428 (S)-2-Methyl-10-[3-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-naphthalen-2-yl-ethyl)-piperazine (854 mg, 3.72 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (895 mg, 3.72 mmol) and 1-methyl-2-pyrrolidinone (8 mL). Heat at reflux. After 5 h, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 576 mg (34%) of the title compound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1). HR-MS calculated for C₂₈H₂₉N₄S: 453.2113. Found 453.2116. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.

Example 429 (S)-2-Methyl-10-[4-methyl-3-(2-naphthalen-2-yl-ethyl-)piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Add formaldehyde (101 μL, 1.28 mmol, 37% in water) to a solution of (S)-2-methyl-10-[3-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (525 mg, 1.16 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (369 mg, 1.7 mmol) and stir 1 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 550 mg (100%) of the title compound: mass spectrum (ion spray): m/z=467 (M+1), 465 (M−1). HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.

Example 430 (S)-2-Methyl-10-[4-methyl-3-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Crystallize the dihydrochloride salt from ethyl acetate and ethanol to give the title compound: mp 209° C. dec. Mass spectrum (ion spray): m/z=467 (M+1), 465 (M−1). Analysis calculated for C₂₉H₃₂Cl₂N₄S: C, 64.56; H, 5.98; N, 10.38. Found: C, 64.18; H, 5.74; N, 10.28. HR-MS calculated for C₂₉H₃₁N₄S: 467.2269. Found 467.2243. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.

Example 431 (S)-1,4-Dibenzyl-2-(2-furan-3-yl-ethyl-piperazine

Combine 9-borabicyclo[3.3.1]nonane (165.8 mL, 82.9 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine (6.06 g, 20.7 mmol) and stir at ambient temperature. After 24 h, add triphenylphosphine (1.74 g, 6.6 mmol), tetrakis(triphenylphosphine) palladium(0) (958 mg, 0.83 mmol) and 3-bromofuran (2.8 mL, 31.1 mmol). Add 3M NaOH (17.0 mL, 51.0 mmol) slowly, gas evolution occurs. Heat at reflux. After 24 h, add tetrakis(triphenylphosphine) palladium(0) (958 mg, 0.83 mmol). After 48 h, cool to ambient temperature and concentrate under reduced pressure. Add 2.5N NaOH (200 mL), and stir 30 min. Extract with diethyl ether. Filter the precipitate and discard. Extract the diethyl ether extracts with 1N sulfuric acid. Make basic with 5N sodium hydroxide and extract with diethyl ether, dry over sodium sulfate, filter and concentrate. Purify by silica gel chromatography using ethyl acetate/hexanes (10%) as the eluent to give 2.4 g of a mixture of the title compound and (S)-1,4-dibenzyl-2-ethyl-piperazine: mass spectrum (ion spray): m/z=361 (M+1, (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine), m/z=295 (M+1, (S)-1,4dibenzyl-2-ethyl-piperazine).

Example 432 (S)-2-(2-Furan-3-yl-ethyl)-piperazine

Dissolve a mixture of (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine and (S)-1,4-dibenzyl-2-ethyl-piperazine (2.29 g, 6.35 mmol) in 1,2-dichloroethane (10 mL). Cool on an ice bath and add 1-chloroethyl chloroformate (2.06 ml, 19.1 mmol) dropwise. Remove ice bath and heat to 83° C. for 5.5 h. Concentrate the reaction, dissolve the residue in methanol (50 mL) and heat to reflux for 2 h. Cool to ambient temperature and stir 18 h. Filter and concentrate to a solid. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%–10%) as the eluent to give 330 mg (29%) of the title compound: mp 112–4° C. Mass spectrum (ion spray): m/z=181 (M+1).

Example 433 (S)-2-(2-Furan-3-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine (810 mg, 2.25 mmol) in ethanol (5 mL). Add ammonium formate (850 mg, 13.5 mmol) and palladium (100 mg, 5 wt. % on carbon) and heat to reflux. After 3.5 h, filter the palladium and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (5%) as the eluent to give 175 mg (43%) of the title compound: mass spectrum (ion spray): m/z=181 (M+1). Analysis calculated for C₁₀H₁₆N₂O: C, 66.63; H, 8.95; N, 11.54. Found: C, 66.53; H, 8.92; N, 11.14.

Example 434 (S)-10-[3-(2-Furan-3-yl-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-furan-3-yl-ethyl)-piperazine (550 mg, 3.05 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (700 mg, 3.05 mmol), toluene (6 mL) and DMSO (1.5 mL). Heat at 100° C. After 48 h, cool to ambient temperature and dilute with ethyl acetate. Filter the solids and dilute the filtrate with water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 282 mg (24%) of the title compound: mass spectrum (ion spray): m/z=393 (M+1), 391 (M-1). HR-MS calculated for C₂₂H₂₅N₄OS: 393.1749. Found 393.1742. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure.

Example 435 (S)-10-[3-(2-Furan-3-yl-ethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Add formaldehyde (49 μL, 0.61 mmol, 37% in water) to a solution of (S)-10-[3-(2-furan-3-yl-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (219 mg, 0.56 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (177 mg, 0.56 mmol) and stir 1 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–2.5%) as the eluent to give 179 mg (79%) of the title compound: mass spectrum (ion spray): m/z=407 (M+1), 405 (M−1). HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure;

Example 436 (S)-10-[3-(2-Furan-3-yl-ethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Crystallize the dihydrochloride salt from ethyl acetate and ethanol to give the title compound: mp 198° C. dec. Mass spectrum (ion spray): m/z=407 (M+1), 405 (M−1). Analysis calculated for C₂₃H₂₈Cl₂N₄OS.0.3H₂O: C, 56.97; H, 5.95; N, 11.56. Found: C, 56.73; H, 5.69; N, 11.48. HR-MS calculated for C₂₃H₂₇N₄OS: 407.1906. Found 407.1892. HPLC: Symmetry Cis column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.3 min; 100% pure.

Example 437 (S)-1,4-Dibenzyl-2-(2-thiophen-3-yl-ethyl)-piperazine

Combine 9-borabicyclo[3.3.1]nonane (54.7 mL, 27.4 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and stir at ambient temperature. After 24 h, add triphenylphosphine (574 mg, 2.2 mmol), tetrakis(triphenylphosphine) palladium(0) (316 mg, 0.27 mmol) and 3-iodothiophene (1.93 g, 9.2 mmol). Add 3M NaOH (5.6 mL, 16.8 mmol) slowly, gas evolution occurs. Heat at reflux. After 48 h, cool to ambient temperature, add 5N HCl (12 mL), and stir 1 h. Extract with ethyl acetate and wash the extracts with 1N NaOH, water, brine, dry over sodium sulfate, filter and concentrate. Purify by silica gel chromatography using ethyl acetate/hexanes (10%) as the eluent to give 2.38 g of the title compound as an adduct of 9-BBN: mass spectrum (ion spray): m/z=377 (M+1).

Example 438 (S)-2-(2-Thiophen-3-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-thiophen-3-yl-ethyl)-piperazine (1.17 g, 3.1 mmol) and (S)-1,4-dibenzyl-2-(2-thiophen-2-yl-ethyl)-piperazine (230 mg, 0.61 mmol) in 1,2-dichloroethane (10 mL). Add 1-chloroethyl chloroformate (2.0 ml, 18.5 mmol) and heat to 80° C. for 18 h. Concentrate the reaction, dissolve the residue in methanol and heat to reflux for 2 h. Concentrate to an oil. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (10%) then 7N ammonia in methanol-methylene chloride (10%) as the eluent to give 400 mg (55%) of a 6:1 mixture of the title compound to (S)-2-(2-thiophen-2-yl-ethyl)-piperazine: mass spectrum (ion spray): m/z=197 (M+1).

Example 439 (S)-2-Methyl-10-[3-(2-thiophen-3-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Add methyl trifluoromethanesulfonate (241 μL, 2.13 mmol) to a 0° C. slurry of 2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (437 mg, 1.77 mmol) in dichloromethane (5 mL). Stir 2 h at 0° C. then warm to ambient temperature and stir 16 h. Concentrate the reaction to an orange powder. Add a 6:1 mixture of (S)-2-(2-thiophen-3-yl-ethyl)-piperazine and (S)-2-(2-thiophen-2-yl-ethyl)-piperazine (346 mg, 1.76 mmol) and pyridine (5 mL). Heat to reflux for 7.5 h and stir at ambient temperature for 18 h. Concentrate the reaction, dissolve the residue in methanol-dichloromethane, apply to a SCX column. Wash the column with methanol-dichloromethane to remove impurities then elute the product with 2N ammonia in methanol-methanol (10%). Concentrate and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 333 mg of a brown foam. Purify by radial silica gel chromatography using a 4 mm plate and 1% isopropylamine in tetrahydrofuran-hexanes (10%–20%) as the eluent to give 218 mg (30%) of the title compound: mass spectrum (ion spray): m/z=409 (M+1), 407 (M −1). HR-MS calculated for C₂₂H₂₅N₄S₂: 409.1521. Found 409.1540. ¹H NMR (DMSO-d₆): δ 7.56 (s, 1H), 7.43 (dd, 1H), 7.13 (s, 1H), 6.99 (d, 1H), 6.87–6.74 (m, 3H), 6.67 (d, 1H), 6.31 (s, 1H), 3.88 (br d, 1H), 3.76 (br d, 1H), 2.88 (br d, 1H), 2.80–2.53 (m, 5H), 2.45–2.38 (m, 1H), 2.27 (s, 3H), 1.61 (dd, 2H).

Example 440 (S)-2-Methyl-10-[4-methyl-3-(2-thiophen-3-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

Add formaldehyde (45 μL, 0.56 mmol, 37% in water) to a solution of (S)-2-methyl-10-[3-(2-thiophen-3-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (210 mg, 0.51 mmol) in methylene chloride (6 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (163 mg, 0.77 mmol) and stir 2h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (2%) as the eluent to give 127 mg (59%) of the free base of the title compound. Crystallize the dihydrochloride salt from ethyl acetate and ethanol to give the title compound: mass spectrum (ion spray): m/z=423 (M+1), 421 (M−1). Analysis calculated for C₂₃H₂₈Cl₂N₄S₂.0.2HCl.0.3H₂O: C, 54.35; H, 5.71; N, 11.01; Cl, 15.35. Found: C, 54.10; H, 5.34; N, 10.99; Cl, 15.00. HR-MS calculated for C₂₃H₂₇N₄S₂423.1677. Found 423.1656.

By the method of Example 59, the following compounds were prepared and isolated as the free base:

No. R′ Data 441 CH₂Ph ¹H NMR(CDCl₃)δ1.19(d, 6H), 2.58–3.04(m, 8H), 3.98(m, 1H), 4.09(m, 1H), 4.97(s, 1H), 6.24(s, 1H), 6.60(d, 1H), 6.87(t, 1H), 6.97(t, 1H), 7.02(d, 1H), 7.18–7.36(m, 5H); MS (APCI)m/z(rel intensity)417(100). Product is yellow powder. 442 CH₂CH₂Ph ¹H NMR(CDCl₃)δ1.23(d, 6H), 1.65–1.82(m, 3H), 2.58–2.97(m, 7H), 3.05(m, 1H), 3.99(m, 1H), 4.11(m, 1H), 4.98(s, 1H), 6.31(s, 1H), 6.60(d, 1H), 6.87(t, 1H), 6.97(t, 1H), 7.04(d, 1H), 7.20–7.32(m, 5H); MS(APCI)m/z(rel intensity)431(100). 10 mg of product. 443 CH₂(2-OCH₃)Ph mp 85–97° C.; ¹H NMR(CDCl₃)δ1.18(d, 3H), 1.20(d, 3H), 2.76–2.61(m, 2H), 2.92–2.79(m, 3H), 3.11–2.95(m, 3H), 3.82(s, 3H), 4.05–3.96(m, 2H), 4.98(s, 1H), 6.24(s, 1H), 6.60(d, 1H), 6.91–6.84(m, 3H), 6.96(ddd, 1H), 7.02(d, 1H), 7.17(d, 1H), 7.21(ddd, 1H); MS(APCI)m/z(rel intensity)447.3(100). 22% yield.

By the method of Example 90, the following compounds were prepared and isolated as the free base and the (S) isomer:

No. R′ Data 444 CH₂CH₂Ph ¹H NMR(CDCl₃)δ1.24(d, 6H), 1.75(septet, 1H), 1.93–2.03(m, 2H), 2.21(m, 1H), 2.35 (s, 1H), 2.38(m, 1H), 2.58(m, 1H), 2.74(m, 1H), 2.88(m, 1H), 2.96(m, 1H), 3.15(ddd, 1H), 3.93(m, 1H), 4.06(m, 1H), 4.98(s, 1H), 6.34(s, 1H), 6.61(d, 1H), 6.88(t, 1H), 6.98(t, 1H), 7.05(d, 1H), 7.17–7.32(m, 5H); MS (APCI)m/z(rel intensity)445(100). 220 mg of product. 444a CH₂Ph ¹H NMR(CDCl₃)δ1.11(d, 3H), 1.12(d, 3H), 2.40–2.49(m, 3H), 2.50(s, 3H), 2.77(septet, 1H), 2.85(m, 1H), 2.90(ddd, 1H), 3.16(m, 1H), 3.22(m, 1H), 3.63(m, 1H), 3.93(m, 1H), 4.92(s, 1H), 6.07(s, 1H), 6.57(d, 1H), 6.85(t, 1H), 6.92–6.97(m, 2H), 7.14–7.27 (m, 5H); MS(APCI)m/z(rel intensity)431 (100). 252 mg of product. 444b CH₂(2-OCH₃—Ph) mp 79–89° C.: ¹H NMR(CDCl₃)δ1.10(d, 3H), 1.12(d, 3H), 2.50–2.40(m, 3H), 2.52(s, 3H), 2.77(m, 1H), 2.96–2.86(m, 2H), 3.21(d, 1H), 3.24(bt, 1H), 3.61(d, 1H), 3.78(s, 3H), 3.92(bd, 1H), 4.92(s, 1H), 6.07(s, 1H), 6.57(d, 1H), 6.87–6.79(m, 3H), 6.95–6.92(m, 2H), 7.07(d, 1H), 7.17(ddd, 1H); MS(APCI)m/z(rel intensity)461.3(100). 93% yield.

Example 445 (S)-2-tert-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

By using a method similar to the method of Example 460, using 2-tert-butyl4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (0.934 g, 3.44 mmol) and (S)-2-phenethyl-piperazine (0.655 g, 3.44 mmol) gives 0.561 g of the title compound as a yellow solid: mp 93–96° C.; mass spectrum (ion spray): m/z=445 (M+1); Analysis for C₂₇H₃₂N₄S(0.5 H₂O): calcd: C, 71.49; H, 7.33; N, 12.35; found: C, 71.27; H, 6.88; N, 12.29.

Example 446 (S)-2-tert-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-2-tert-butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene (0.429 g, 0.96 mmol) gives 0.229 g of the title compound as a yellow solid: mp 230° C.; mass spectrum (ion spray): m/z=459 (M+1); Analysis for C₂₈H₃₆Cl₂N₄S(1.5 H₂O): calcd: C, 60.20; H, 7.04; N, 10.03; found: C, 60.57; H, 7.26; N, 10.22.

Example 447 5-Amino-2-methyl-thiazole-4-carboxylic acid ethyl ester

Add acetoamidoacetate (1000 g, 5.88 mol) to a 22 L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer then add toluene (12 L). Add to this suspension at RT Lawesson's reagent (1187 g, 2.93 mol). Stir the resulting yellow slurry at 70° C. for 16 h, cool to RT. Pour the top yellow solution away from the gummy material on the bottom of the flask into a separation funnel. Add 1N HCl solution (2.5 L) and TBEA (2.5 L) and stir the mixture. After 15 min., combine the bi-phase solution was into the toluene solution in the funnel. Gummy material maybe left in the flask. Repeat the above procedure again. Separate the aqueous and wash the combine organic solution with 1N HCl (2×2.5 L). Separate the organic layer and combine the aqueous and basify with 2N KOH solution. Add ethyl acetate (3×4 L) and extract the product. Combine the organic layer, dry over anhydrous sodium sulfate, and evaporate to give 552 g as a pale yellow solid. Dissolve the remaining gummy in methanol (1 L) and evaporate to dryness. Add MTBE (2.5 L) and 1N HCl (4 L) and stir the mixture. After 15 min., separate the organic layer and basify the aqueous with 2N KOH solution Extract the product with ethyl acetate (2×2 L). Combine the organic layers and dry over anhydrous sodium sulfate and evaporate to give 165 g as a pale yellow solid. (Total: 717 g, 65%). Mass spectrum (m/e): 187 (M+1); ¹HNMR(300 MHz, DMSO, ppm): 1.21 (t, 3H), 2.38 (s, 3H), 4.21 (q, 2H), 7.21 (bs, 2H). ¹³CNMR(75MHz, DMSO, ppm):, 15.1, 19.2, 59.8, 119.3, 145.6, 161.7, 164.1. Formula: C₇H₁₀N₂O₂S.

Example 448 2-Methyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl ester

Add a solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (120 g; 645 mmol) and 2-fluoronitrobenzene (68 mL; 645 mmol) in dimethylsulphoxide (1 L) to a 2 L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer. Add lithium hydroxide monohydrate (54 g; 1290 mmol) to the solution and heat at 50° C. for 3 hours under nitrogen. Cool the purple solution and pour onto ice/water, allow to stir for one hour, filter and wash with water, dry at 50° C. under reduced pressure to give 190 g (96%) as an orange solid: mass spectrum (m/e): 308 (M+1); ¹HNMR(300 MHz, DMSO, ppm): 1.25 (tr, 3H), 2.56 (s, 3H), 4.25 (q, 2H), 7.20 (m, 1H), 7.78 (m, 2H), 8.20 (d, 1H), 11.42 (s, 1H, NH). ¹³CNMR(75 MHz, DMSO, ppm): 24.4, 29.2, 71.2, 127.8, 132.5, 132.8, 137.8, 146.5, 147.0, 147.5, 160.2, 161.5, 173.7. Formula: C₁₃H₁₃N₃O₄S.

Example 449 2-Methyl-5-(2-nitrophenylamino)-thiazole-4-carboxylic acid amide

Combine ethyl 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylate (80 g, 260 mmol) and formamide (52 mL, 1.3 mol) in DMF (200 mL) and heat to 105° C. which time the yellow slurry became a dark solution. Add to this reaction mixture at 105° C. dropwise 25% sodium methoxide in methanol (40 mL, 182.4 mmol) during 45 min period and heat to 115° C. and continue stir for 60 h. Cool the reaction to RT, pour into a cold saturated NaHCO₃ solution. Stir the resulting slurry for 1 h, filter and wash the solid with DMF/H₂O (2:1). Dry in a vacuum oven, to obtain a dark brown solid (62 g, 86%). Another batch starting 100 g of ethyl 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylate to give 82 g (90%) of crude product: mass spectrum (m/e): 279 (M+1); ¹HNMR(300 MHz, DMSO, ppm): 2.5 (s, 3H), 7.05 (m, 1H), 7.51 (d, 1H), 7.65 (m, 2H), 8.10 (d, 1H), 12.18 (s, 1H). ¹³CNMR(75 MHz, DMSO, ppm): 19.4, 116.8, 121.7, 127.3, 129.9, 136.3, 137.0, 137.8, 145.6, 151.2, 166.1. Formula: C₁₁H₁₀N₄O₃S.

Example 450 2-Methyl-5-(2-nitro-phenylamino)-thiazole-4-carbonitrile

Combine 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylic acid amide (60 g, 215 mmol) and toluene and add POCl₃ (40 mL, 430 mmol) and reflux the reaction mixture. After 2.5 h cool to 0° C. Add saturated NaHCO₃ solution to quench the extra POCl3 (Caution!!) until the aqueous was around pH 8. Add ethyl acetate (2×2 L) to extract the product. Combined organic layer and wash with brine (2×1 L), dry over MgSO₄, and evaporate to give a reddish solid which triturated with 25% ethyl acetate in hexane to give a reddish solid (36 g). Evaporate the filtrate to half volume to give second batch of compound (3.2 g). Total yield (39.2 g, 70%): mass spectrum (m/e): 261 (M+1); ¹HNMR(300 MHz, DMSO, ppm): 2.70 (s, 1H), 7.02 (t, 1H), 7.22 (d, 1H), 7.58 (t, 1H), 8.25 (d, 1H), 9.78 (s, 1H). ). ¹³CNMR(75MHz, DMSO, ppm): 20.4, 113.1, 116.2, 118.7, 121.2 127.0, 134.9, 136.6, 140.0, 148.6, 161.5. Formula: C₁₁H₈N₄O₂S

Example 451 2-Methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine hydrochloride

Combine a suspension of 2-methyl-5-(2-nitroanilino)thiazole-4-nitrile (36 g,; 138.5 mmol) in isopropanol (400 ml) in a 2.0 liter 3-necked RB flask equipped with a reflux condenser, thermometer, magnetic stirrer bar and heat with stirring to 65° C. (orange solution obtained). Add tin (II) chloride hydrate (78.7 g; 415.4 mmol) in hydrochloric acid (400 ml; 5M) and heat the resulting solution at reflux. After 2.5 h., cool the reaction to 15° C., filter the suspension, wash with isopropanol/water (2:1) and dry at 50° C. under reduced pressure to leave a yellow solid (36.7 g). Evaporate the filtrate to around 200 mL to form a yellow slurry. Filter the slurry again and dry at 50° C. under reduced pressure to leave a yellow solid (10 g). Combine the solid and suspend in 1 N HCl (700 mL) and heat to reflux for 20 min, cool to 15° C. Filter the resulting yellow slurry and dry at 50° C. under reduced pressure to leave a yellow solid (32.4 g, 88%): mass spectrum (m/e): 231 (M+1); ¹HNMR(300 MHz, DMSO, ppm): 2.5 (s, 3H), 6.78 (dd, 1H), 6.85 (dd, 1H), 6.98 (t, 1H), 7.02 (t, 1H), 8.80 (s, 1H), 9.10 (s, 1H), 9.98 (s, 1H), 10.78 (s, 1H). ¹³CNMR(75 MHz, DMSO, ppm): 19.6, 120.1, 120.8, 123.6, 125.8, 127.8, 129.2, 137.6, 154.4, 159.3, 160.4. Formula C₁₁H₁₁N₄S.

Example 452 Cyano-isobutyrylamino-acetic acid ethyl ester

Dilute aqueous saturated sodium bicarbonate (560 mL) with deionized water (700 mL). and stir the solution while adding ethyl cyanoglyoxylate-2-oxime (70.0 g, 493 mmol) in portions (note: some off-gassing and a gentle endotherm were observed). Add sodium dithionite (238 g, 1.37 mol, 2.8 eq.) in portions and stir at rt. After 2.5–3 hours, during this time the reaction was monitored by TLC (EtOAc, I₂ stain), saturate the solution with sodium chloride (400 g), and extract the product CH₂Cl₂ (1×500 mL, 3×250 mL), making sure solid NaCl was visible (more added if necessary) during the extractions. Combine the organic layers, dry over (MgSO₄), filter, and concentrate the filtrate to dryness in vacuo on a rotovapor at low bath temperature (30–35° C.) to afford 19.6 g (31%) crude amino-cyano-acetic acid ethyl ester which was used immediately in the next reaction.

Cool a solution of amino-cyano-acetic acid ethyl ester (19.0 g, 148 mmol) in CH₂C₁₂ (300 mL) to 0–5° C. under N₂. Add pyridine (12.0 mL, 148 mmol) followed by isobutyric anhydride (24.6 mL, 148 mmol). Allow the reaction solution to warm to rt overnight until complete by TLC (EtOAc). Wash the solution with aqueous 1N HCl, water, aq. sat'd NaHCO₃, then brine (150 mL each). Dry the organic layer over MgSO₄, filter, and concentrate the filtrate to dryness in vacuo on a rotovapor to a solid. Triturate the solid with Et₂O (500 mL), filter and dry (50° C. vacuum oven) to afford 22.0 g (75%) of the title compound: ¹H NMR (300 MHz, DMSO-d₆) δ 9.05 (d, 1H, J=7.32 Hz), 5.67 (d, 1H, J=7.32 Hz), 4.25–4.13 (m, 2H), 2.46 (dq, 1H, J=6.95 Hz), 1.21 (t, 3H, J=6.95 Hz), 1.03 (d, 6H, J=6.95 Hz). ¹³C NMR (75 MHz, DMSO-d₆) δ 176.51, 164.13, 115.60, 62.33, 44.07, 33.29, 18.93, 18.86, 13.74. IR (CHCl₃) 3425, 3028, 2975, 2933, 2905, 2874, 1757, 1687,1492, 1370, 1284, 1189 cm⁻¹. HRMS (FAB+) M/z calculated for C₉H₁₅N₂O₃ (M+H) 199.1083 found 199.1075.

Example 453 Cyano-isobutyrylamino-acetic acid ethyl ester

Combine ethyl cyanoglyoxylate-2-oxime (20.0 g, 141 mmol) and 5% Pt/C (2.0 g, 10% wt. load) in acetic acid (120 mL) and EtOAc (60 mL) and hydrogenate under 40 psi H₂ overnight until the reaction is complete by TLC (5:1/heptane:EtOAc, I₂ stain). Carefully filtered the spent catalyst using partial vacuum through glass fiber paper, and rinse with HOAc/EtOAc without allowing the cake to dry out. Concentrate the filtrate in vacuo on a rotovapor to an oil, leaving 25.5 g (96%) of crude amino-cyano-acetic acid ethyl ester as the HOAc salt. Partition a portion (13.0 g) of the HOAc salt between EtOAc (70 mL) and-water (35 mL). Stir the biphasic solution and add dropwise aqueous 5N NaOH (1 6.5 mL) to adjust the pH to 8.0–8.2. Separate the layers, and extract the aqueous layer with more EtOAc (3×25 mL). Combine the organic layer, dry (MgSO₄), filter, and concentrate the filtrate to dryness in vacuo on a rotovapor at low bath temperature (30–35° C.) to afford 5.68 g (65%) crude amino-cyano-acetic acid ethyl ester which was used immediately in the next reaction.

Cool a solution of crude amino-cyano-acetic acid ethyl ester (5.68 g, 44.3 mmol) in CH₂Cl₂ (60 mL) to 0–5° C. under N₂. Add pyridine (3.60 mL, 44.5 mmol), followed by isobutyric anhydride (7.40 mL, 44.6 mmol). Allow the reaction solution to warm to rt overnight (18 h) until complete by TLC (3:1/EtOAc:heptane, 12 stain, co-spot needed to distinguish between SM and impurity). Wash the solution with aqueous 1N HCl, water, aq. sat'd NaHCO₃, then brine (50 mL each). Dry the organic layer (MgSO₄), filter, and concentrate the filtrate to dryness in vacuo on a rotovapor to a solid. Triturate the solid with Et₂O (150 mL), filter and dry (50° C. vacuum oven) to afford 4.33 g (49%) of the title compound.

Example 455 5-Amino-2-isopropyl-thiazole-4-carboxylic acid ethyl ester

Stir cyano-isobutyrylamino-acetic acid ethyl ester (139 g, 701 mmol) mechanically stir as a slurry in toluene (1.4 L) at rt under N₂. Add lawesson's reagent (170 g, 420 mmol, 0.6 eq.) in portions and heat the thick slurry to 70° C. and stir for 12 hours until complete by TLC (2:1/heptane:THF). Cool the mixture and concentrate to dryness in vacuo on a rotovapor to obtain 353 g of thick yellow oil that was partially purified by silica gel plug (1 Kg silica gel 60, 1.5 vol. warm 2:1/THF:heptane as diluent, 2:1/heptane:THF as eluent). Combine the product containing filtrates and concentrate to dryness in vacuo on a rotovapor to obtain 194 g of crude solid. Dissolve the solid in EtOAc (400 mL) at 50–60° C. with stirring, then allow to cool gradually to rt. Precipitate the product and was cool to 0–5° C. with stirring for 30 minutes, isolate by suction filtration, rinse with cold EtOAc (2×50 mL), then dry in a vacuum oven at 50° C. to afford a first crop of 76.3 g (51%) of the title compound. Obtain a second crop of 17.6 g (12%)=from the filtrate after concentration in vacuo and silica gel chromatography (1 Kg silica gel 60, 2:1/heptane:THF). ¹H NMR (300 MHz, DMSO-d₆) δ 7.23 (bs, 2H), 4.21 (q, 2H, J=6.95 Hz), 3.02 (dq, 1H, J=6.95 Hz), 1.27 (t, 3H, J=6.95 Hz), 1.22 (d, 6H, J=6.95 Hz). ¹³C NMR (75 MHz, DMSO-d₆) δ 163.72, 160.08, 156.20, 118.08, 58.99, 32.27, 22.35 (2), 14.46. IR (CHCl₃) 3483, 3347, 2975,2933, 2868, 1668, 1582, 1530, 1494, 1464, 1409, 1382 cm⁻¹. HRMS (ES) M/z calculated for C₉H₁₄N₂O₂S 215.0854, found 215.0842.

Example 456 2-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl ester

Combine a solution of 5-amino-2-isopropyl-thiazole-4-carboxylic acid ethyl ester (8.71 g, 40.6 mmol) and 2-fluoronitrobenzene (4.28 mL, 40.6 mmol) in DMSO (105 mL) and stir at rt under N₂ as LiOH (1.95 g, 81.4 mmol, 2.0 eq.) or LiOH monohydrate (2 eq) is added in one portion. The reaction turns dark. Heat the reaction mixture to 55° C. for 3 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). Cool to rt overnight, Cool the reaction to 0–5° C. with stirring as deionized water (315 mL) is added at such a rate to maintain the temperature below 20° C. Precipitate the product and the reaction color changes from brown to rust-orange color. Stir the slurry for 3–4 h at rt, filter by vacuum and rinse with minimal 3:1/H₂O: DMSO, dry in a vacuum oven at 60° C. to afford 12.4 g (91%) of the title compound as an orange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.52 (bs, 1H), 8.23 (d, 1H, J=8.05 Hz), 7.80 (m, 2H), 7.21 (m, 1H), 4.36 (q, 2H, J=7.32 Hz, 6.95 Hz), 3.23 (dq, 1H, J=6.95 Hz), 1.34 (m, 9H). ¹³C NMR (75 MHz, DMSO-d₆) δ 163.22, 161.85, 149.08, 136.99, 136.37, 136.10, 126.53, 126.48, 121.94, 117.05, 60.45, 32.47, 22.34(2), 14.24. IR (CHCl₃) 2976, 2932, 2867, 1709, 1677, 1611, 1580, 1550, 1512, 1415, 1340 cm⁻¹. HRMS (ES) M/z calculated for C₁₅H₁₇N₃O₄S 336.1018, found 336.1009.

Example 457 2 Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid amide

Stir 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl ester (68.6 g, 204 mmol) at rt under N₂ as a slurry in DMF (205 mL). Add formamide (32.4 mL, 816 mmol, 4.0 eq.) in one portion, and heat the thick red slurry to 100° C.; a dark red/purple solution is formed. Add dropwise over 20–30 min, 25% NaOMe in MeOH (32.6 mL, 143 mmol, 0.7 eq.) Increase the temperature 120° C. and stir the dark solution was stirred at 120° C. overnight until complete (<2% Me ester+SM) by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). After cooling the reaction to rt, add aqueous 5% NH₄Cl (410 mL) at such a rate as to maintain the temperature below 35° C. with no external cooling. Precipitate the product, cool the slurry to 0–5° C., filter by vacuum filtration and dry in a vacuum oven at 60° C. to afford 52.7 g (84% yield) crude title compound as a purple solid that was used without further purification. An aqueous workup may result in bad emulsions/slow separations. ¹H NMR (300 MHz, DMSO-d₆) δ 12.22 (bs, 1H), 8.21 (d, 1H, J=7.69 Hz), 7.78 (m, 2H), 7.59 (bs, 1H), 7.53 (bs, 1H), 7.15 (m, 1H), 3.23 (dq, 1H, J=6.95 Hz), 1.35 (d, 6H, J=6.95 Hz). ¹³C NMR (75 MHz, DMSO-d₆) δ 165.53, 161.44, 144.58, 137.12, 136.31, 135.72, 128.90, 126.58, 121.08, 116.28, 32.32, 22.35(2). IR (CHCl₃) 3520, 3400, 3004, 2967, 2925, 2866, 1658, 1611, 1578, 1513, 1427, 1342 cm⁻¹. HRMS(ES) M/z calculated for C₁₃H₁₄N₄O₃S₁ 329.0684, found 329.0667.

Example 458 2-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carbonitrile

Combine 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid amide (47.5 g, 155 mmol) and 2-dichloroethane (475 mL) and stir at rt under N₂ as a dark solution. Pour POCl₃ (14.5 mL, 155 mmol) into the solution, and heat the reaction to reflux (80–83° C.) for 2–3 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 L/min). Coolthe reaction to rt, cool further to 0–5° C. Adjust the pH to 8–9 by adding aqueous 2N NaOH (275 mL) at such a rate to maintain the temperature below 20° C. Separate the layers, extract the aqueous layer with CH₂Cl₂ (2×100 mL). Combine the organic layer, wash with brine (2×100 mL), dry (MgSO₄), filter, and concentrate the filtrate in vacuo to a dark oil/solid residue (40 g). Purify the crude product by silica gel chromatography (1200 g silica gel 60, CH₂Cl₂) to afford 29.4 g (66%) of the title compound as a red solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.78 (bs, 1h), 8.15 (dd, 1H, J=6.95 Hz, 1.46 Hz), 7.67 (dt, 1H, J=7.32 Hz, 1.46 Hz), 7.26 (dd, 1H, J=7.32 Hz, 1.10 Hz), 7.15 (dt, 1H, J=6.95 Hz, 1.10 Hz), 3.26 (dq, 1H, J=6.95 Hz), 1.33 (d, 6H, J=6.95 Hz). ¹³C NMR (75 MHz, DMSO-d₆) δ 171.85, 150.83, 139.10, 136.22, 136.00, 126.05, 121.41, 118.64, 116.09, 113.73, 33.01, 22.07(2). IR (CHCl₃) 3311, 3021, 2970, 2928, 2868, 2223, 1613, 1583, 1518, 1492, 1448, 1403, 1341 cm⁻¹. HRMS (ES) M/z calculated for C₁₃H₁₂N₄O₂S 289.0759, found 289.0744.

Example 459 2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine hydrochloride

Combine 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carbonitrile (35.1 g, 122 mmol) and IPA (525 mL) stir under N₂ and heat to 60° C. to dissolve. Add a solution of SnCl₂ (70.0 g, 369 mmol, 3.0 eq.) in aqueous 5M HCl (525 mL) dropwise over 30 min. Heat the reaction mixture at reflux (80–85° C.) for 1 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). Cooling the reaction to 50° C. Remove most of the solvent in vacuo. Treat the aqueous solid residue (188 g) with IPA (500 mL) and heat to 60–70° C. for a few minutes to form a homogenous slurry. Cool the slurry to rt, then 0–5° C. for 1–2 h. Isolate the product by vacuum filtration and dry in a vacuum oven at 60° C. to afford 45.9 g (128%) of crude product that was heavily contaminated with residual tin. Suspent the crude product in aqueous 1N HCl (2.25 L) and heat to reflux (95° C.) for 1 h, during which time most of the solids dissolve. Cool to rt, isolate the product by vacuum filtration, rinse with aqueous 1N HCl, and dry in a vacuum oven at 70° C. to afford 34.5 g (97%) of the title compound as a yellow/orange solid. Analytical analysis: Sn (9.0%), H₂O (1.2%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.96 (bs, 1H), 10.15 (bs, 1H), 8.94 (bs, 2H), 7.10–6.95 (m, 2H), 6.93–6.82 (m, 2H), 3.10 (dq, 1H, J=6.95 Hz), 1.28 (s, 3H), 1.26 (s, 3H). ¹³C NMR (75 MHz, DMSO-d₆) δ 164.42, 159.24, 158.94, 137.01, 128.58, 127.11, 125.09, 122.87, 120.14, 119.23, 32.41, 21.98(2). IR(KBr) 3301, 3249, 2964, 1653, 1614, 1553, 1509 cm⁻¹. HRMS (ES) M/z calculated for C₁₃H₁₅N₄S 259.1017 (M⁺−Cl), found 259.1010.

Example 460 (S)-2-Methyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride hemihydrate

Combine 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.712 g, 3.09 mmol)(preparation described in Eur. Pat. Appl. EP 354781(1990) and (S)-2-phenethyl-piperazine (0.588 g, 3.09 mmol) in NMP (6.0 mL) and heat at 200° C. for 3 hours. Cool to ambient temperature and dilute with water (75 mL). Extract with ethyl acetate to give 1.11 g. of the crude product. Silica gel chromatography, eluting with methylene chloride: 2N NH₃/methanol (100:5), gives 0.756 g of the title compound as the free base. The dihydrochloride salt precipitates in ethyl acetate as a tan solid: mp 230° C.; mass spectrum (ion spray): m/z=404 (M+1); Analysis for C₂₃H₂₇Cl₂N₅S(0.5 H₂O): calcd: C, 56.90; H, 5.81; N, 14.43; found: C, 56.61; H, 5.63; N, 14.21.

Example 461 (S)-2-Methyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride hemihydrate

Combine (S)-2-methyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.5 g, 1.24 mmol) and 37% Formaldehyde solution (0.1 mL, 1.36 mmol)in 1,2-dichloroethane (25 mL). Stir for 10 minutes and add sodium triacetoxy borohydride (0.394, 1.86 mmol). Stir an additional 30 minutes and then pour solution onto saturated Sodium bicarbonate solution. Extract with methylene chloride to give 0.52 g of the crude product. Silica gel chromatography, eluting with methylene chloride: 2N NH₃/methanol (100:3), gives 0.296 g of the title compound as the free base. The dihydrochloride salt precipitates in ethyl acetate as a yellow solid: mp 220° C.; mass spectrum (ion spray): m/z=418 (M+1); Analysis for C₂₄H₂₉Cl₂N₅S(0.5 H₂O): calcd: C, 57.71; H, 6.05; N, 14.02; found: C, 57.81; H, 6.08; N, 13.81.

Example 462 (S)-10-(3-Benzyl-piperazin-1-yl-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By a similar method to Example 460, using 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.703 g, 3.0 mmol) and (S)-2-benzyl-piperazine (0.538 g, 3.0 mmol) give 0.410 g of the title compound as a yellow solid: mp 250–252° C.; mass spectrum (ion spray): m/z=390 (M+1); Analysis for C₂₂H₂₃N₅S(0.6 H₂O): calcd: C, 66.01; H, 6.09; N, 17.49; found: C, 65.94; H, 5.66; N, 17.8 1.

Example 463 (S)-10-[3-(2-Methoxy-benzyl)-piperazin-1-yl]-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By a similar method to the method of Example 460, using 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.687 g, 2.98 mmol) and (S)-2-(2-methoxy-benzyl)-piperazine (0.615 g, 2.98 mmol) gives 0.437 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=420 (M+1); Analysis for C₂₃H₂₅N₅OS(0.5 H₂O): calcd: C, 64.46; H, 6.12; N, 16.34; found: C, 64.20; H, 5.77; N, 16.14.

Example 464 (S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Combine (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (180 mg, 0.82 mmol), 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (188 mg, 0.82 mmol), 1-methyl-2-pyrrolidinone (5 mL). Heat at 195° C. After 3.75 h, cool to ambient temperature and stir 18 h. Combine with another 2.30 mmol reaction executed under same conditions. Dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%–4%) as the eluent to give 388 mg (29%) of the title compound: mass spectrum (ion spray): m/z=434 (M+1), 432 (M−1). HR-MS calculated for C₂₄H₂₈N₅OS: 434.2015. Found 434.201 HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure.

Example 465 (S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Add formaldehyde (86 μL, 1.09 mmol, 37% in water) to a solution of (S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (430 mg, 0.99 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (315 mg, 1.49 mmol) and stir 1 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–3%) as the eluent to give 400 mg (90%) of the free base of the title compound. Crystallize the dihydrochloride salt from ethyl acetate and ethanol to give the title compound: mass spectrum (ion spray): m/z=448 (M+1), 446 (M−1). Analysis calculated for C₂₅H₃₁Cl₂N₅OS.0.3H₂O: C, 57.09; H, 6.06; N, 13.32. Found: C, 56.98; H, 6.17; N, 12.93. HR-MS calculated for C₂₅H₃₀N₅OS: 448.2171. Found 448.2177. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure.

Example 466 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By a similar method to the method of Example 460, using 2-methyl4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.21 g, 5.25 mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (1.09 g, 5.25 mmol) to give 0.848 g of the title compound as a tan solid: mass spectrum (ion spray): m/z=422 (M+1); Analysis for C₂₃H₂₄FN₅S(0.3 H₂O): calcd: C, 64.70; H, 5.81; N, 16.40; found: C, 64.97; H, 5.86; N, 16.15.

Example 467 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method to the method of Example 460, using 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.25 g, 5.42 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (1.13 g, 5.42 mmol) gives 1.06 g of the title compound as a tan solid: mass spectrum (ion spray): m/z=422 (M+1); Analysis for C₂₃H₂₄FN₅S(0.2 H₂O): calcd: C, 64.98; H, 5.78; N, 16.47; found: C, 65.18; H, 5.91; N, 16.17.

Example 468 (S)-2-Isopropyl-10-(3-phenethyl-piperazin-1-yl)4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.47 g, 5.69 mmol) and (S)-2-phenethyl-piperazine (1.08 g, 5.69 mmol) to give 1.04 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=432 (M+1); Analysis for C₂₅H₂₉N₅S: calcd: C, 69.57; H, 6.77; N, 16.22; found: C, 69.40; H, 6.90; N, 15.98.

Example 469 (S)-2-Isopropyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method of the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.48 g, 5.7 mmol) and (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (1.26 g, 5.7 mmol) to give 1.01 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=462 (M+1); Analysis for C₂₆H₃₁N₅OS(0.3 H₂O): calcd: C, 66.87; H, 6.82; N, 15.00; found: C, 66.58; H, 6.35; N, 14.96.

Example 470 (S)-10-(3-Benzyl-piperazin-1-yl)-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method of the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.44 g, 5.5 mmol) and (S)-2-benzyl-piperazine (0.983 g, 5.5 mmol) to give 0.580 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=418 (M+1); Analysis for C₂₄H₂₇N₅S(0.2 H₂O): calcd: C, 68.44; H, 6.56; N, 16.63; found: C, 68.63; H, 6.43; N, 16.74.

Example 471 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (0.566 g, 2.19 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.457 g, 2.19 mmol) to give 0.539 g of the title compound as a solid: mass spectrum (ion spray): m/z=450 (M+1); Analysis for C₂₅H₂₈FN₅S(0.2 H₂O): calcd: C, 66.26; H, 6.32; N, 15.45; found: C, 65.96; H, 6.11; N, 15.31.

Example 472 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Stir 2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (0.551 g, 2.0 mmol) in dichloromethane (10.0 mL) and chilled in an ice bath while adding methyl trifluoromethane sulfonate (0.27 mL, 2.4 mmol). Allow this solution to stir at ambient temperature for 16 hours. Evaporate the solvent to a gray solid. Dissolve this solid and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.417 g, 2.0 mmol) in pyridine (8.0 mL) and heat at 115° C. for 23 hours. After evaporation of the pyridine, silica gel chromatography, eluting with methylene chloride: 2N NH₃/methanol (100:5), gives 0.354 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=450 (M+1); Analysis for C₂₅H₂₈FN₅S(0.2 H₂O): calcd: C, 66.26; H, 6.32; N, 15.45; found: C, 66.01; H, 6.15; N, 15.25.

Example 473 (S)-10-(3-Benzyl-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, (S)-10-(3-benzyl-piperazin-1-yl)-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.355 g, 0.91 mmol) gives 0.407 g of the title compound as a yellow solid: mp 240° C.; mass spectrum (ion spray): m/z=404 (M+1); Analysis for C₂₃H₂₇Cl₂N₅S(0.5 H₂O): calcd: C, 56.90; H, 5.81; N, 14.43; found: C, 56.74; H, 5.85; N, 14.23.

Example 474 (S)-10-[3-(2-Methoxy-benzyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-10-[3-(2-methoxy-benzyl)-piperazin-1-yl]-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.388 g, 0.92 mmol) gives 0.452 g of the title compound as an orange solid: mp 185° C.; mass spectrum (ion spray): m/z=434 (M+1); Analysis for C₂₄H₂₉Cl₂N50S(2.1 H₂O): calcd: C, 52.96; H, 6.15; N, 12.87; found: C, 52.84; H, 5.75; N, 12.49.

Example 475 (S)-2-Isopropyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-2-isopropyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.950 g, 2.2 mmol) gives 0.686 g of the title compound as an orange solid: mp 210° C.; mass spectrum (ion spray): m/z=446 (M+1); Analysis for C₂₆H₃₃Cl₂N₅S(1.2 H₂O): calcd: C, 57.81; H, 6.61; N, 12.97; found: C, 58.07; H, 6.55; N, 12.56.

Example 476 (S)-2-Isopropyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-2-isopropyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.932 g, 2.0 mmol) gives 0.770 g of the title compound as a yellow solid: mp 190° C.; mass spectrum (ion spray): m/z=476 (M+1); Analysis for C₂₇H₃₅Cl₂N₅OS(0.2 H₂O): calcd: C, 58.73; H, 6.46; N, 12.68; found: C, 58.44; H, 6.01; N, 12.58.

Example 477 (S)-10-(3-Benzyl-4-methyl-piperazin-1-yl)-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-10-(3-benzyl-piperazin-1-yl)-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.517 g, 1.23 mmol) gives 0.491 g of the title compound as a yellow solid: mp 235° C.; mass spectrum (ion spray): m/z=432 (M+1); Analysis for C₂₅H₃₁Cl₂N₅S(1.0 H₂O): calcd: C, 57.46; H, 6.37; N, 13.40; found: C, 57.18; H, 5.80; N, 13.39.

Example 478 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.776 g, 1.84 mmol) gives 0.694 g of the title compound as a yellow solid: mp 230° C.; mass spectrum (ion spray): m/z=436 (M+1); Analysis for C₂₄H₂8Cl₂FN₅S(0.7 H₂O): calcd. C, 55.32; H, 5.69; N, 13.44; found: C, 55.20; H, 5.63; N, 13.36.

Example 479 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.951 g, 2.25 mmol) gives 0.841 g of the title compound as a yellow solid: mp 230° C.; mass spectrum (ion spray): m/z=436 (M+1); Analysis for C₂₄H₂₈Cl₂FN₅S(0.5 H₂O): calcd C, 55.70; H, 5.65; N, 13.53; found: C, 55.94; H, 5.65; N, 13.37.

Example 480 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.4301 g, 0.95 mmol) gives 0.440 g of the title compound as an orange solid: mp 180° C.; mass spectrum (ion spray): m/z=464 (M+1).

Example 481 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using (S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.316 g, 0.7 mmol) gives 0.338 g of the title compound as an orange solid: mp 228° C.; mass spectrum (ion spray): m/z=464 (M+1); Analysis for C₂₆H₃₂Cl₂FN₅S(0.6 H₂O): calcd: C, 57.05; H, 6.11; N, 12.80; found: C, 56.72; H, 5.73; N, 12.54.

Example 482 Pentanoic acid (2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-amide

Add valeryl chloride (3.92 mL, 33.0 mmol) dropwise to a solution of 3-Amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (5.74 g, 30.0 mmol) and triethylamine (4.60 mL, 33.0 mmol) in anhydrous dimethylformamide (123 mL) and stir. After 6 hours, concentrate under reduced pressure to a residue and reconstitute the residue in a solution of isopropanol:chloroform (1:3, 500 mL). Stir overnight to give a solid and isolate the solid by suction filtration, washing the solid with dichloromethane. Vacuum dry the solid at ambient temperature 2 hours to afford the title compound. Wash the filtrate with a saturated aqueous solution of sodium bicarbonate (2×200 mL), and filter the extraction mixture to remove salt formed in the wash. Separate the organic phase and wash it with saturated aqueous sodium chloride (150 mL). Back extract the bicarbonate aqueous phase with dichloromethane. Combine all organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Triturate the residue in diethyl ether, filter the resulting solid, and wash it with diethyl ether; repeat 2×. Dry the solid at ambient temperature under vacuum to give the title compound: mass spectrum (APCI, m/e): 276 (M+1); ¹H NMR (300 MHz, DMSO-d₆): 10.68 (s, 2H), 8.23 (d, 1H, J=7.5 Hz), 7.20 (m, 4H), 4.71 (d, 1H, J=7.5 Hz), 2.25 (t, 2H, J=7.5 Hz), 1.43 (m, 2H), 1.25 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).

Example 483 2-Butyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

Combine pentanoic acid (2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-amide (4.13 g, 15.0 mmol) and Lawesson's reagent (9.10 g, 22.5 mmol) in anhydrous dichloroethane (250 mL), heat to 85° C., and stir. After 16 hours, cool to ambient temperature, collect the reaction solid by suction filtration, and dry the solid at ambient temperature under vacuum to give the title compound: mass spectrum (APCI, m/e): 290 (M+1); ¹H NMR (300 MHz, DMSO-d₆) 10.95 (s, 1H), 9.01 (s, 1H), 6.93 (m, 3H), 6.71 (d, 1H, J=7.5 Hz), 2.68 (t, 2H, J=7.5 Hz), 1.53 (m, 2H), 1.30 (m, 2H), 0.85 (t, 3H, J=7.5 Hz).

Example 484 (S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add methyl trifluoromethanesulfonate (0.850 mL, 7.51 mmol) to a 0° C. solution of 2-Butyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (1.45 g, 5.01 mmol) in anhydrous dichloromethane. Rinse solids into reaction with dichloromethane and stir allowing reaction to slowly reach ambient temperature. After an overnight period, concentrate under reduced pressure to afford crude methylated intermediate. Take 1.06 g of this intermediates (2.0 mmol), and combine the intermediate and 2-(S)-Phenethyl-piperazine (0.38 g, 2.0 mmol), with anhydrous pyridine, heat to 100° C. and stir. After an overnight period, cool to ambient temperature and concentrate under reduced pressure to an oil (2.16 g), followed by two chromatographic purifications, eluting with a gradient of a 8% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane), gives the title compound (0.078 g). Mass spectrum (APCI+, m/e): 446 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 7.79 (s, 1H), 7.31–7.10 (m, 5H), 6.90–6.74 (m, 3H), 6.71–6.64 (m, 1H), 4.14–3.92 (br. m, 1H), 3.44–3.22 (m, 1H), 2.93–2.52 (m, 10H), 1.65–1.49 (m, 4H), 1.36–1.20 (m, 2H, J=7.1 Hz), 0.82 (t, 3H, J=7.1 Hz).

Example 485 (S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Add a solution of acetyl chloride (0.0601 mL, 0.842 mmol) in absolute ethanol at ambient temperature to (S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.075 g, 0.17 mmol) in absolute ethanol, with added drops of methanol to solubilize the freebase, stir and concentrate under reduced pressure to give the title compound (0.078 g): Mass spectrum (ES+, m/e): 446 (M+1−2HCl); exact mass spectrum (ES+, m/e, C₂₆H₃₁N₅S.2HCl): calc. 446.2378 (M+1–2HCl), found 446.2397.

Example 486 (S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1 yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add sodium triacetoxyborohydride and aqueous formaldehyde (37%w/w, to a solution of (S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.50 g, 1.1 mmol) in dichloroethane (12 mL) and stir. After 5 hours, dilute with a saturated aqueous solution of sodium bicarbonate, and separate the layers. Extract the aqueous layer with dichloromethane (3×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to an oil (0.24 g). Purify the oil by flash chromatography, eluting with a gradient of a 5% solution of 2M ammonia in methanol, in dichloromethane (0–100% over 30 minutes), and then with a 5% solution of 2M ammonia in methanol, in dichloromethane to give the title compound (0.19 g): Mass spectrum (APCI+, m/e): 460 (M+1); ¹H NMR (300 MHz, CDCl₃), δ (ppm): 7.39–7.11 (m, 5H), 7.11–6.95 (m, 2H), 6.94–6.81 (m, 1H), 6.69–6.57 (m, 1H), 5.01 (s, 1H), 4.40–3.93 (br. m, 1H), 3.34–3.16 (m, 1H), 3.08–2.92 (m, 1H), 2.93–2.40 (m, 7H), 2.40–2.23 (m, 4H), 2.06–1.51 (m, 4H), 1.38 (d, 2H, J=7.1 Hz), 0.90 (t, 3H, J=7.1 Hz).

Example 487 (S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Add a solution of acetyl chloride (0.15 mL, 2.1 mmol) in absolute ethanol at ambient temperature to (S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.19 g, 0.41 mmol) in absolute ethanol, with added drops of methanol to solubilize the freebase, and concentrate under reduced pressure gives the title compound (0.18 g). Mass spectrum (APCI+, m/e): 460 (M+1−2HCl); exact mass spectrum (ES+, m/e, C₂₇H₃₃N₅S.2HCl): calc. 460.2535 (M+1−2HCl), found 460.2556.

Example 488 Cyclopentanecarboxylic acid (2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazapin-3-yl)-amide

Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (7.0 g, 36.6 mmol) and triethyl amine (4.07 g, 40.3 mmol) in 120 mL DMF and add dropwise cyclopentanecarbonyl chloride (5.34 g, 40.3 mmol) at RT. After stirring overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl₃/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO₃ (sat.2×100 mL) and dry with Na₂SO₄. Concentrate the the solvent to give second crop of title compound, total 9.13 g, yield 87%: ¹H NMR (300 MHz, DMSO-d₆): 10.70 (s, 2H), 8.11 (d, 1H, J=7.8 Hz), 7.24–7.15 (m, 4H), 4.73 (d, 1H, J=7.5 Hz), 2.96–2.87 (m, 1H), 1.74–1.45 (m, 8H).

Example 489 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

Combine cyclopentanecarboxylic acid (2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazapin-3-yl)-amide (1.90 g, 6.6 mmol) and Lawesson's reagent (4.01 g, 9.9 mmol) in 120 mL 1,2-dichloroethane and heat to reflux under N₂. Cool the reaction to RT, after 4 hour, collect 1.56 g orange solid via suction filtration, yield 78%. ¹H NMR (400 MHz, DMSO-d₆): 10.96 (s, 1H), 9.05 (s, 1H), 7.00–6.89 (m, 3H), 6.78–6.76 (m, 1H), 3.21–3.10 (m, 1H), 2.00–1.90 (m, 2H), 1.7–1.55 (m, 6H).

Example 490 2-Cyclopentyl-10-(4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Combine N-methyl piperazine (0.264 g, 2.64 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.205 g, 0.66 mmol) in 7 ml of pyridine, and heat to reflux over night. Cool to room temperature, remove pyridine, the residue purify on silica gel using 2N ammonia in methanol/ dichloromethane (1:10) as the eluent to give 165 mg foam, which recrystallize in methanol to give 110 mg of title compound: Mass spectrum (electrospray) (m/e): C₂₀H₂₅N₅S, Cacl. Mass (M): 367.18, Found: 368.18 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 6.97–6.90 (m, 2H), 6.81 (dt, 1H, J=7.3 Hz, J=1.0 Hz), 6.55 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 4.96 (br, 1H), 3.2–3.17 (m, 1H), 2.49–2.47 (m, 4H), 2.28 (s, 3H), 2.03–1.97 (m, 2H), 1.71–1.55 (m, 10H).

Example 491 (S)-2-Cyclopentyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Combine (S)-2-phenethyl-piperazine (0.537 g, 3.0 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.451 g, 1.5 mmol) in 10 ml of pyridine, and heat to 85° C. for 20 hour. Cool to room temperature, remove pyridine, the residue purify on silica gel using 2N ammonia in methanol/dichloromethane (1:10) as the eluent to give 265 mg of title compound as yellow solid. Mass spectrum (electrospray) (m/e): C₂₇H₃₁N₅S, Cacl. Mass: 457.2; Found: 458.3 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.31–7.27 (m, 2H), 7.24–7.16 (m, 3H), 7.05–6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz), 6.62 (dd, 1H, J=7.8 Hz, J=1.0 Hz), 5.00 (br, 1H), 4.25 (br, 1H), 3.25 (t, 1H, J=7.8 Hz), 3.02–2.88 (m, 4H), 2.73–2.63 (m, 3H), 2.07–2.03 (m, 2H), 1.77–1.61 (m, 10H).

Example 492 (S)-2-Cyclopentyl-10-(3-phenethyl-4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Combine 2-cyclopentyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (220 mg, 0.48 mmol), formaldehyde (37%, w/w, aq) (47 mg, 0.58 mmol) and sodium triacetoxyborohydride (152.6 mg, 0.72 mmol) in 12 mL 1,2-dichloroethane and stir at RT for 4 hours. Quench the reaction by adding water, then extract with CH₂Cl₂, dry the combined organic solvents over Na₂SO₄. The crude material purify by flash chromatography on silica gel, gradient 100% CH₂Cl₂ to 100% mixed solvent of (15% 2N ammonia in methanol of dichloromethane) over 55 min, give 225 mg yellow foam, 2-Cyclopentyl-10-(3-phenethyl-4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene. The dihydrochloric salt is form by adding 3 eq of acetyl chloride (111.4 mg, 1.42 mmol) to the free base (223 mg, 0.437 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 15 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 235 mg of orange solid. Mass spectrum (electrospray) (m/e): C₂₈H₃₃N₅S, Cacl. Mass: 471.2; Found: 472.2 (M+1).

Example 493 (S)-2-Cyclopentyl-10-(3-benzyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to the method of Example 491, using (S)-2-benzyl-piperazine (1.23 g, 7.0 mmol), 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.602 g, 2.0 mmol) in 8 ml of pyridine Obtain 240 mg light brown foam of title compound. Mass spectrum (electrospray) (m/e): C₂₆H₂₉N₅S, Cacl. Mass: 443.36; Found: 444.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.32–7.21 (m, 5H), 7.03–6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz), 6.61 (d, 1H, J=7.8 Hz), 5.00 (br, 1H), 3.21–2.90 (m, 4H), 2.78–2.72 (m, 1H), 2.62–2.56 (m, 1H), 2.03–1.95 (m, 2H), 1.77–1.62 (m, 10H).

Example 494 (S)-2-Cyclopentyl-10-(3-benzyl-4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, dihydrochloride

Using a method similar to the method of Example 492, using (S)-2-cyclopentyl-10-(3-benzyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (185 g, 0.418 mmol), formaldehyde (37%, w/w, aq) (42.3 mg, 0.52 mmol) and sodium triacetoxyborohydride (132 mg, 0.63 mmol) in 5 mL 1,2-dichloroethane and stir at RT for 5 hours After purification, give 157 mg of free base as yellow solid: mass spectrum (electrospray) (m/e): C₂₇H₃₁N₅S, Calc. Mass: 457.23; Found: 458.1 (M+1); The dihydrochloric salt is form by adding 3 eq of acetyl chloride (77.3 mg, 0.98 mmol) to the free base (150 mg, 0.33 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 176 mg of orange solid.

Example 495 (S)-2-Cyclopentyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the method of Example 491, using (S)-2-(3-methoxy-phenyl)-piperazine (1.10 g, 5.0 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.540 g, 1.79 mmol) in 6 ml of pyridine, and heat to 85° C. for 5 hour. After purification, give 310 mg of title compound as brown solid. Mass spectrum (electrospray) (m/e): C₂₈H₃₃N₅OS, Cacl. Mass: 487.24; Found: 488.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.21–7.17 (m, 1H), 7.05–6.97 (m, 2H), 6.86 (dt, 1H, J=7.3 Hz, J=1.9 Hz), 6.79–6.72 (m, 3H), 6.61 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 5.00 (br, 1H), 4.25 (br, 1H), 3.78 (s, 3H), 3.02–2.89 (m, 4H), 2.69–2.63 (m, 3H), 2.07–2.04 (m, 2H1), 1.77–1.48 (m, 10M).

Example 496 (S)-2-Cyclopentyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, dihydrochloride

By using the method similar to the Example 492, using (S)-2-cyclopentyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, (270 mg, 0.55 mmol), formaldehyde (37%, w/w, aq) (0.56 g, 0.69 mmol) and sodium triacetoxyborohydride (174.8 mg, 0.825 mmol) in 8 mL 1,2-dichloroethane and stir at RT. After purification, give 230 mg of free base as brown oil. Mass spectrum (electrospray) (m/e): C₂₉H₃₅N₅OS, Cacl. Mass: 501.26; Found: 502.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.21–7.17 (m, 1H), 7.06–6.96 (m, 2H), 6.87 (dt, 1H, J=7.8 Hz, J=1.5 Hz), 6.79–6.72 (m, 3H), 6.62 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 5.05 (br, 1H), 3.78 (s, 3H), 3.27–3.21 (m, 1H), 3.02–2.72 (m, 3H), 2.60–2.42 (m, 2H), 2.38–2.28 (m, 4H), 2.12–1.83 (m, 3H), 1.76–1.60 (m, 10H). The dihydrochloric salt is form by adding 3 eq of acetyl chloride (105.8 mg, 1.37 mmol) to the free base (225 mg, 0.45 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 252 mg of orange solid.

Example 497 (S)-2-Cyclopentyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Slowly add (S)-2-(4-methoxy-phenyl)-piperazine (440 mg, 2.0 mmol) in 5.0 mL of pyridine to 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo {f}azulene-10-thione (602 mg, 2.0 mmol) in 5 ml of pyridine over 2.5 h at 85° C., then stir for 5 h at 85° C. Cool to RT, remove the solvent, the residue purified on silica gel, using gradient (dichloromethane to 15% of 2N ammonia in methanol/dichloromethane), give 450 mg of title compound. Mass spectrum (electrospray) (m/e): C₂₈H₃₃N₅OS, Cacl. Mass: 487.24; Found: 488.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.11–6.97 (m, 4H), 76.89–6.81 (m, 3H), 6.63 (m, 1H), 5.02 (br, 1H), 4.25 (br, 1), 3.78 (s, 3H), 3.26–3.23 (m, 1H), 2.99–2.88 (m, 41), 2.68–2.62 (m, 3H), 2.10–2.03 (m, 2H), 1.76–1.16 (m, 10H).

Example 498 (S)-2-Cyclopentyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, dihydrochloride

By using a method similar to the method of Example 492, using (S)-2-Cyclopentyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, (220 mg, 0.45 mmol), formaldehyde (37%, w/w, aq) (45.8 mg, 0.56 mmol) and sodium triacetoxyborohydride (143 mg, 0.675 mmol) in 5 mL 1,2-dichloroethane and stir at RT. After purification, give 200 mg of free base as brown oil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.11–6.97 (m, 4H), 6.89–6.80 (m, 3H), 6.61 (dd, 1H, J=7.8 Hz, J=1.0 Hz), 5.02 (br, 1H), 3.78 (s, 3H), 3.27–3.21 (m, 1H), 3.02–2.60 (m, 2H), 2.56–2.42 (m, 2H), 2.34–2.28 (m, 5H), 2.12–2.06 (m, 2H), 1.95–1.83 (m, 1H), 1.77–1.61 (m, 10H). The dihydrochloric salt is form by adding 3 eq of acetyl chloride (94.2 mg, 1.20 mmol) to the free base (200 mg, 0.40 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 223 mg of title compound as orange solid.

Example 499 N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazapin-3-yl)-propionamide

Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (5.7 g, 30.0 mmol) and triethyl amine(3.33 g, 33.0 mmol) in 120 mL DMF and add propionyl chloride (3.05 g, 33.0 mmol) dropwise at RT. After stirring overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl₃/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO₃ (sat.2×100 mL) and dry with Na₂SO₄. Concentrate the organic solvent down to a residue, treat with ether, collect the solid as title compound: mass spectrum (APCI) (m/e): 248.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆): 10.70 (s, 2H), 8.19 (d, 1H, J=7.2 Hz), 7.23–7.15 (m, 4H), 4.73 (d, 1H, J=8.0 Hz), 2.27 (q, 2H, J=8.0 Hz), 0.94 (t, 3H, J=8.0 Hz).

Example 500 2-Ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

Combine N-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazapin-3-yl)-propionamide (3.7 g, 15.0 mmol) and Lawesson's reagent (9.09 g, 22.5 mmol) in 225 mL 1,2-dichloroethane, heat to reflux under N₂. After refluxing overnight, cool the reaction to RT, collect the orange solid via suction filtration, and dry under vacuum to obtain 3.3 g crude material. Take crude material (1.0 g), mix with Lawesson's reagent (0.75 g) in 1,2-dichloroethane (30 mL), heat to reflux overnight, cool to RT, collect the orange-red solid via suction filtration to obtain the title compound. Treat the remaining of the intermediate similarly (2.3 g) to obtain additional title compound: mass spectrum (electrospray) (m/e): 261.8 (M+1), 260.0 (M−1); ¹H NMR (300 MHz, DMSO-d₆): 10.97 (s, 1H), 9.17 (s, 1H), 7.00–6.91 (m, 3H), 6.79–6.70 (m, 1H), 2.73 (q, 2H, J=7.5 Hz), 1.16 (t, 3H, J=7.5 Hz),

Example 501 (S)-2-Ethyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add methyl trifluoromethanesulfonate (4.2 g, 26.0 mmol) overnight, to a suspension of 2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo {f}azulene-10-thione (3.4 g, 13.0 mmol) in 35 mL CH₂Cl₂, LC-MS showed still had 50% of starting material, added another 0.1 mL of methyl trifluoromethanesulfonate, and heated to 35° C. for 1 h. Concentrate the reaction mixture under reduced pressure to give a red-brown solid. Dissolve the solid in 32.5 mL of pyridine to make 0.4 M of solution. Take 5 mL of the solution (2.0 mmol), mix with (S)-2-(4-methoxy-phenyl)-piperazine (440 mg, 2.0 mmol) and heat to 100° C. for 2.5 hours. Cool the reaction to RT, concentrate down to a residue, which purify by flash chromatography on silica gel, gradient 100% CH₂Cl₂ to 100% mixed solvent of (CH₂Cl₂: 2N NH₃/MeOH=20:1) over 55 min. give 250 mg of the title compound. Mass spectrum (APCI) (m/e): C₂₅H₂₉N₅OS, Cacl. Mass: 447.21, Found: 448.2 (M+1); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.12–6.80 (m, 7H), 6.68–6.65 (m, 1H), 5.30 (br, 1H), 4.25 (m, 2H), 3.77 (s, 3H), 3.21–2.88 (m, 4H), 2.85–2.79 (m, 3H), 2.67–2.62 (m, 2H), 1.77–1.75 (m, 2H), 1.29 (t, 3H, J=7.3 Hz).

Example 502 (S)-2-Ethyl-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-benzo[f]azulene

By using a method similar to the method of Example 501, using a suspension of 2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo {f}azulene-10-thione (3.4 g, 13.0 mmol) in 35 mL CH₂Cl₂, add methyl trifluoromethanesulfonate (4.2 g, 26.0 mmol) overnight, LC-MS showed still had 50% of starting material, added another 0.1 mL of methyl trifluoromethanesulfonate, and heated to 35° C. for 1 h. Concentrate the reaction mixture under reduced pressure, give a red-brown solid. Dissolve the solid in 32.5 mL of pyridine to make 0.4 M of solution. Take 6.25 mL of the solution (2.5 mmol), mix with (S)-2-(4-fluoro-phenyl)-piperazine (520 mg, 2.5 mmol) and heat to 100° C. for 3 hours. Cool the reaction to RT, concentrate down to a residue, which purify by flash chromatography on silica gel, gradient 100% CH₂Cl₂ to 100% mixed solvent of (CH₂Cl₂:2N NH₃/MeOH=20:1) over 55 min. give 360 mg of the title compound as orange-brown foam. Mass spectrum (APCI) (m/e): C₂₄H₂₆FN₅S, Cacl. Mass: 435.15, Found: 436.2 (M+1); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.17–6.86 (m, 7H), 6.66–6.63 (m, 1H), 5.30 (br, 1H), 4.25–4.15 (m, 2H), 3.10–2.66 (m, 10H), 1.76–1.71 (m, 2H), 1.28 (t, 3H, J=7.7 Hz).

Example 503 (S)-2-Ethyl-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the method of Example 501, using a suspension of 2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (3.4 g, 13.0 mmol) in 35 mL CH₂Cl₂, add methyl trifluoromethanesulfonate (4.2 g, 26.0 mmol) overnight, LC-MS showed still had 50% of starting material, added another 0.1 mL of methyl trifluoromethanesulfonate, and heated to 35° C. for 1 h. Concentrate the reaction mixture under reduced pressure, give a red-brown solid. Dissolve the solid in 32.5 mL of pyridine to make 0.4 M of solution. Take 6.25 mL of the solution (2.5 mmol), mix with (S)-2-(3-fluoro-phenyl)-piperazine (520 mg, 2.5 mmol) and heat to 100° C. for 3 hours. Cool the reaction to RT, concentrate down to a residue, which purify by flash chromatography on silica gel, gradient 100% CH2C12 to 100% mixed solvent of (CH₂Cl₂: 2N NH₃/MeOH=20:1) over 55 min. give 412 mg of the title compound Mass spectrum (APCI) (m/e): C₂₄H₂₆FN₅S, Cacl. Mass: 435.15, Found: 436.2 (M+1); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.24–6.85 (m, 7H), 6.66–6.65 (m, 1H), 5.30 (br, 1H), 4.25–4.15 (m, 2H), 3.20–2.68 (m, 10H), 1.90–1.75 (m, 2H), 1.29 (t, 3H, J=7.3 Hz).

Example 504 (S)-2-Ethyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the Example 501, using a suspension of 2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (3.4 g, 13.0 mmol) in 35 mL CH₂Cl₂, add methyl trifluoromethanesulfonate (4.2 g, 26.0 mmol) overnight, LC-MS showed still had 50% of starting material, added another 0.1 mL of methyl trifluoromethanesulfonate, and heated to 35° C. for 1 h. Concentrate the reaction mixture under reduced pressure, give a red-brown solid. Dissolve the solid in 32.5 mL of pyridine to make 0.4 M of solution. Take 6.25 mL of the solution (2.5 mmol), mix with (S)-2-(3-methoxy-phenyl)-piperazine (550 mg, 2.5 mmol) and heat to 100° C. for 3 hours. Cool the reaction to RT, concentrate down to a residue, which purify by flash chromatography on silica gel, gradient 100% CH2Cl₂ to 100% mixed solvent of (CH₂Cl₂: 2N NH₃/MeOH=20:1) over 55 min. give 306 mg of the title compound. Mass spectrum (APCI) (m/e): C₂₅H₂₉N₅OS, Cacl. Mass: 447.21, Found: 448.2 (M+1); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.21–7.16 (m, 1H), 7.08–6.96 (m, 2H), 6.91–6.86 (m, 1H), 6.80–6.71 (m, 3H), 6.65–6.64 (m, 1H), 5.40 (br, 1H), 4.35–4.25 (m, 2H), 3.78 (s, 3H), 3.16–2.69 (m, 10H), 1.79–1.76 (m, 2H), 1.29 (t, 3H, J=7.7 Hz).

Example 506 (S)-2-Ethyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, dihydrochloride

By using a similar method to Example 492, using (S)-2-ethyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, (190 mg, 0.42 mmol), formaldehyde (37%, w/w, aq) (42.7 mg, 0.53 mmol) and sodium triacetoxyborohydride (134.9 mg, 0.64 mmol) in 5 mL 1,2-dichloroethane and stir at RT. After purification, give 145 mg of free base as brown oil: mass spectrum (APCI) (m/e): C₂₆H₃₁N₅OS, Cacl. Mass: 461.22, Found: 462.2(M+1); The dihydrochloric salt is form by adding 5 eq of acetyl chloride (115 mg, 1.46 mmol) to the free base (135 mg, 0.292 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 142 mg of title compound as orange solid.

Example 507 (S)-2-Ethyl-10-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

By using a method similar to Example 492, using (S)-2-ethyl-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, (292 mg, 0.67 mmol), formaldehyde (37%, w/w, aq) (68 mg, 0.84 mmol) and sodium triacetoxyborohydride (213 mg, 1.01 mmol) in 6 mL 1,2-dichloroethane and stir at RT. After purification, give 272 mg of free base as yellow solid. Mass spectrum (APCI) (m/e): C₂₅H₂₈FN₅S, Cacl. Mass: 449.15, Found: 450.2; The dihydrochloric salt is form by adding 5 eq of acetyl chloride (115 mg, 1.46 mmol) to the free base (135 mg, 0.292 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 300 mg of title compound as yellow solid.

Example 508 (S)-2-Ethyl-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

By using a method similar to Example 492, using (S)-2-ethyl-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, (236 mg, 0.54 mmol), formaldehyde (37%, w/w, aq) (55 mg, 0.68 mmol) and sodium triacetoxyborohydride (172 mg, 0.81 mmol) in 6 mL 1,2-dichloroethane and stir at RT. After purification, give 140 mg of free base: mass spectrum (APCI) (m/e): C₂₅H₂₈FN₅S, Cacl. Mass: 449.20, Found: 450.2 (M+1); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.24–7.19 (m, 1H), 7.07–6.84 (m, 6H), 6.64–6.61 (m, 1H), 5.29 (br, 1H), 4.35–4.25 (m, 2H), 3.27–3.23 (m, 1H), 3.04–2.71 (m, 5H), 2.62–2.42 (m, 2H), 2.33–2.29 (m, 4H), 2.00–1.74 (m, 2H), 1.29 (t, 3H, J=7.7 Hz). The dihydrochloric salt is form by adding 5 eq of acetyl chloride (122 mg, 1.56 mmol) to the free base (140 mg, 0.31 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 139 mg of title compound as orange solid.

Example 509 (S)-2-Ethyl-10-{3-[2-(3-methoxy-2-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

By using a method similar to the method of Example 492, using (S)-2-ethyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene, (252 mg, 0.56 mmol), formaldehyde (37%, w/w, aq) (57 mg, 0.70 mmol) and sodium triacetoxyborohydride (179.2 mg, 0.85 mmol) in 5 mL 1,2-dichloroethane and stir at RT. After purification, give 215 mg of free base. Mass spectrum (APCI) (m/e): C₂₆H₃₁N₅OS, Cacl. Mass: 461.22, Found: 462.2(M+1); The dihydrochloric salt is form by adding 5 eq of acetyl chloride (168.8 mg, 2.15 mmol) to the free base (200 mg, 0.43 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 225 mg of title compound.

Example 510 N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2,2,2-trifluoro-acetamide

Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.67 g, 40.0 mmol), and 4-(dimethylamino)pyridine (0.244 g, 2.00 mmol) to a solution of 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (7.65 g, 40.0 mmol) in anhydrous N,N-dimethylformamide (50 mL). Rinse solids into reaction with anhydrous N,N-dimethylformamide (50 mL), and cool reaction to 0° C. in an ice/water bath. Add via syringe trifluoroacetic acid (3.08 mL, 40.0 mmol). After 10 minutes, remove cooling, and after 5.5 hours at ambient temperature, add an additional 0.2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g) and trifluoroacetic acid (0.62 mL) and stir at ambient temperature. After an overnight period, concentrate under reduced pressure to give a residue. Reconstitute the residue in isopropanol: chloroform (1:3, 20 mL) and set 5 minutes. Collect solid formed by suction filtration, wash with isopropanol: chloroform (3:1), and dry at ambient temperature under vacuum to give the title compound. Filter the filtrate, which contained precipitated solid and dry this solid at ambient temperature under vacuum to give a second crop of the title compound: mass spectrum (ES neg., m/e): 286.0 (M−1); ¹H NMR (300 MHz, DMSO-d₆): 10.93 (s, 2H), 9.42 (d, 1H, J=6.9 Hz), 7.29–7.15 (m, 4H), 4.91 (d, 1H, J=7.2 Hz).

Example 511 2-Trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

Combine N-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2,2,2-trifluoro-acetamide (3.02 g, 10.5 mmol) with Lawesson's Reagent, [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide], (6.38 g, 15.8 mmol) in anhydrous toluene (60 mL), heat to reflux, and stir. After 16 hours, cool and stir for a few hours. Collect the reaction solid by suction filtration, wash with a small amount of toluene, and dry at 40° C. for a few hours to give crude product (3.6 g). Adsorb material on Silica gel 60 and purify by flash chromatography, eluting with a solution of 35% ethyl acetate in hexane. Combine and concentrate the product-containing fractions under reduced pressure, and dry the product at 54° C. under vacuum for 4.5 hours to give the title compound: mass spectrum (APCI, m/e): 302 (M+1); ¹H NMR (300 MHz, DMSO-d₆): 11.39 (s, 1H), 9.57 (s, 1H), 7.03 (m, 3H), 6.77 (m, 1H).

Example 512 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Following a method similar as described in Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to formed the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine and then (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.62 g, 3.0 mmol), followed by two chromatographic purifications, the first with a pre-packed silica gel column, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane); and the second with a pre-packed cation exchange column, loading with methanol, and then eluting the product with increasing concentrations of 2M ammonia in methanol, in dichloromethane gives the title compound (0.754 g): mass spectrum (APCI+, m/e): 476 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.45 (s, 1H), 7.33–7.23 (m, 1H), 7.05–6.80 (m, 6H), 6.74–6.68 (m, 1H), 4.06–3.80 (br. m, 2.94–2.76 (m, 2H), 2.74–2.52 (m, 5H), 2.35 (br. s, 1H), 1.67–1.49 (m, 2H).

Example 513 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-1-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Add a solution of acetyl chloride (0.566 mL, 7.93 mmol) in absolute ethanol to a solution of (S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.754 g, 1.59 mmol) in absolute ethanol and stir at ambient temperature. Isolate the precipitated solid by suction filtration, washing with diethyl ether to give the title compound (0.660 g): mass spectrum (APCI+, m/e): 476 (M+1−2HCl); exact mass spectrum (ES+, m/e, C₂₃H₂₁F₄N₅S.2HCl): calc. 476.1532 (M+1−2HCl), found 476.1530.

Example 514 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to in Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)-2-[²-(4-fluoro-phenyl)-ethyl]-piperazine (0.62, 3.0 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in ethanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (1.11 g): mass spectrum (APCI+, m/e): 476 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.67–8.36 (m, 2H), 7.27–7.16 (m, 2H), 7.13–7.03 (m, 2H), 7.01–6.86 (m, 3H), 6.75–6.68 (m, 1H), 4.24–3.96 (br. m, 2H), 3.39–2.91 (m, 5H), 2.75–2.51 (m, 2H), 1.88–1.73 (m, 2H).

Example 515 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Using a method similar to Example 513, using (S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.27 g, 0.57 mmol) and a solution of acetyl chloride (0.203 mL, 2.84 mmol) in absolute ethanol at ambient temperature gives the title compound (0.276 g): Exact mass spectrum (ES+, m/e, C₂₃H₂₁F₄N₅S.2HCl): calc. 476.1532 (M+1−2HCl), found 476.1532.

Example 516 (S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)2-[2-(3-Methoxy-phenyl)-ethyl]-piperazine (0.65 g, 3.0 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (0.99 g): mass spectrum (APCI+, m/e): 488 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.73–8.49 (m, 2H), 7.21–7.15 (m, 1H), 6.99–6.88 (m, 3H), 6.79–6.69 (m, 4H), 4.25–3.98 (br. m, 2H), 3.70 (s, 3H), 3.38–3.17 (m, 3H), 3.14–2.97 (m, 2H), 2.74–2.52 (m, 2H), 1.90–1.80 (m, 2H).

Example 517 (S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Using a similar method to the method of Example 513, using (S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.29 g, 0.59 mmol) and a solution of acetyl chloride (0.212 mL, 2.97 mmol) in absolute ethanol at ambient temperature gives the title compound (0.297 g): Exact mass spectrum (ES+, m/e, C₂₄H₂₄F₃N₅OS2HCl): calc. 488.1732 (M+1−2HCl), found 488.1724.

Example 518 (S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.40 g, 1.8 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (0.625 g): mass spectrum (APCI+, m/e): 488 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.58 (s, 1H), 7.13–7.03 (m, 2H), 6.99–6.86 (m, 3H), 6.85–6.78 (m, 2H), 6.75–6.69 (m, 1H), 4.22–3.97 (br. m, 2H), 3.70 (s, 3H), 3.44–2.87 (m, 6H), 2.68–2.46 (m, 2H), 1.84–1.71 (m, 2H).

Example 519 (S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Using a method similar to Example 513, using (S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.252 g, 0.517 mmol) and a solution of acetyl chloride (0.184 mL, 2.58 mmol) in absolute ethanol at ambient temperature gives the title compound (0.258 g): Exact mass spectrum (ES+, m/e, C₂₄H₂₄F₃N₅OS.2HCl): calc. 488.1732 (M+1−2HCl), found 488.1732.

Example 520 (S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add sodium triacetoxyborohydride (0.23 g, 1.1 mmol) and aqueous formaldehyde (37% w/w, 0.083 mL, 1.1 mmol) to a solution of (S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1 yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g, 0.74 mmol) in methanol: dichloroethane (1:1) and stir. After 1.5 hours, concentrate the reaction under reduced pressure to remove methanol, and then dilute with a saturated aqueous solution of sodium bicarbonate and dichloromethane, and separate the layers. Extract the aqueous layer with dichloromethane (2×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol added (40–100% in hexane over 30 minutes, then 100% for 10 minutes) to give the title compound (0.223 g, 60%): mass spectrum (APCI+, m/e): 502 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.48 (s, 1H), 7.19–7.10 (m, 1H), 6.97–6.81 (m, 3H), 6.76–6.67 (m, 4H), 3.96–3.76 (br. m, 2H), 3.68 (s, 3H), 3.15–3.02 (m, 1H), 2.93–2.81 (m, 1H), 2.80–2.69 (m, 1H), 2.65–2.34 (m, 2H), 2.27–2.04 (m, 5H), 1.91–1.75 (m, 1H), 1.66–1.48 (m, 1H).

Example 521 (S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Using a method similar to Example 513, using (S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.223 g, 0.445 mmol) and a solution of acetyl chloride (0.157 mL, 2.22 mmol) in absolute ethanol at ambient temperature gives the title compound. Exact mass spectrum (ES+, m/e, C₂₅H₂₆F₃N₅OS2HCl): calc. 502.1888 (M+1−2HCl), found 502.1885.

Example 522 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Following the method similar to Example 520, using (S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.37 g, 0.78 mmol), sodium triacetoxyborohydride (0.25 g, 1.2 mmol), and aqueous formaldehyde (0.0875 mL, 1.17 mmol) in methanol: dichloroethane gives the title compound (0.213 g): mass spectrum (APCI+, m/e): 490 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.47 (s, 1H), 7.32–7.22 (m, 1H), 7.06–6.81 (m, 6H), 6.75–6.67 (m, 1H), 4.00–3.75 (m, 2H), 3.17–3.03 (m, 1H), 2.93–2.81 (m, 1H), 2.80–2.70 (m, 1H), 2.69–2.40 (m, 2H), 2.29–2.04 (m, 5H), 1.91–1.76 (m, 1H), 1.68–1.51 (m, 1H).

Example 523 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Using a method similar to Example 520, using (S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.213 g, 0.435 mmol) and a solution of acetyl chloride (0.155 mL, 2.18 mmol) in absolute ethanol at ambient temperature gives the title compound: mass spectrum (APCI+, m/e): 490 (M+1−2HCl); exact mass spectrum (ES+, m/e, C₂₄H₂₃F₄N₅S.2HCl calc. 490.1689 (M+1−2HCl), found 490.1686.

Example 524 (S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Following a method similar to the method of Example 520, using (S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g, 0.74 mmol), sodium triacetoxyborohydride (0.23 g, 1.1 mmol), and aqueous formaldehyde (0.083 mL, 1.1 mmol) in methanol: dichloroethane gives the title compound (0.255 g): mass spectrum (APCI+, m/e): 502 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.48 (s, 1H), 7.11–7.00 (m, 2H), 6.97–6.82 (m, 3H), 6.82–6.75 (m, 2H), 6.75–6.68 (m, 1H), 3.96–3.78 (m, 2H), 3.69 (s, 3H), 3.15–3.02 (m, 1H), 2.91–2.67 (m, 2H), 2.61–2.28 (m, 2H), 2.25–2.00 (m,. 5H),.1.88–1.72 (m, 1H), 1.61–1.44 (m, 1H).

Example 525 (S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Using a method similar to the method of 513, using (S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.255 g, 0.508 mmol) and a solution of acetyl chloride (181 mL, 2.54 mmol) in absolute ethanol at ambient temperature gives the title compound (0.269 g): mass spectrum (APCI+, m/e): 502 (M+1−2HCl); exact mass spectrum (ES+, m/e, C₂₅H₂₆F₃N5OS.2HCl): calc. 502.1888 (M+1−2HCl), found 502.1881.

Example 526 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-1,4,9-triaza-benzo[f]azulene

Using a method similar to Example 486, using (S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g, 0.76 mmol) gives partial conversion to the title compound after overnight stirring at ambient temperature. Add another 1.3 equivalents of aqueous formaldehyde (0.074 mL, 0.98 mmol), methanol, and deionized water. After 2.5 hours, concentrate the reaction under reduced pressure to remove methanol and water. Dilute the reaction with a saturated aqueous solution of sodium bicarbonate, and dichloromethane, and separate the layers. Extract the aqueous layer with dichloromethane (2×), combine the organics, and dry (sodium sulfate), filter, and concentrate them under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol added (40–100% in hexane over 30 minutes, then 100% for 10 minutes) to give the title compound (0.392 g). Mass spectrum (APCI+, m/e): 490 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.49 (s, 1H), 7.24–7.13 (m, 2H), 7.11–7.00 (m, 2H), 6.97–6.81 (m, 3H), 6.75–6.68 (m, 1H), 3.96–3.75 (m, 2H), 3.16–3.03 (m, 1H), 2.92–2.80 (m, 1H), 2.79–2.69 (m, 1H), 2.66–2.37 (m, 2H), 2.28–2.01 (m, 5H), 1.89–1.73 (m, 1H), 1.65–1.47 (m, 1H).

Example 527 (S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

Using the method similar to Example 513, using (S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.392 g, 0.801 mmol) and a solution of acetyl chloride (0.286 mL, 4.01 mmol) in absolute ethanol at ambient temperature gives the title compound (0.269 g): mass spectrum (APCI+, m/e): 490 (M+1−2HCl); exact mass spectrum (ES+, m/e, C₂₄H₂₃F₄N₅S.2HCl): calc. 490.1689 (M+1−2HCl), found 490.1690.

Example 528 3-Bromo-2-nitro-benzo[b]thiophene

Add dropwise fuming nitric acid(90%, 8.6 mL, 183 mmol) to a mixture of 3-bromo benzo[b]thiophene (39g, 183 mmol) in TFA(100 mL) and dichloromethane (400mL) at 0° C. The reaction turn greenish, then yellow precipitates. To this reaction mixture, add dichloromethane (200 mL) and the reaction stir at 0° C. for 30 min. Then pour the reaction into ice-water (2 L). Extract with dichloromethane (3×500mL) and the organic layer dry over MgSO4. Evaporation give a yellow solid. The resulting yellow solid triturate with diethyl ether to give a yellow solid. (Total: 34.8 g, 73%). Mass spectrum (m/e): 259 (M+1); ¹HNMR(300 MHz, DMSO-d₆) δ ppm: 7.70 (tt, 2H), 8.04 (d, 1H), 8.17 (d, 1H). ³CNMR(75 MHz, DMSO-d₆) δ ppm: 112.5, 124.8, 126.9, 127.9, 131.3, 137.0, 137.2, 166.1.

Example 529 2-Nitro-Benzo[b]thiophene-3-carbonitrile

Combine 3-bromo-2-nitro-benzo[b]thiophene (33.0 g, 127.4 mmol), copper cyanide (17.1 g, 191.1 mmol) in DMF(150 mL), heat to 120 ° C. for three hours. The reaction cool to RT, pour on ice, then filter. The filter cake wash with dichloromethane. The organic layer separate and dry over MgSO₄, evaporation to give a DMF solution. Add water (400 mL) and the yellow solid precipitate out. After filtration, obtain a brownish solid (23.5 g, 90%). Mass spectrum (m/e): 205 (M+1); ¹HNMR (300 MHz, DMSO-d6) δ: 7.78 (m, 2H), 8.04 (d, 1H), 8.29 (d, 1H). ¹³CNMR(75 MHz, DMSO-d6)δppm: 105.9, 112.1, 125.0, 125.2, 128.8, 131.2, 135.9, 137.8, 158.0.

Example 530 2-Amino-benzo[b]thiophene-3-carbonitrile

Combine in a 500 mL schlenk flask, 2-nitro-benzo[b]thiophene-3-carbonitrile (5.8 g, 28.4 mmol) and Pd/C (3.0 g, 10% w/w, 2.84 mmol) in 1,2-dichloroethane (120 ml), the reaction mixture is charged with a balloon of hydrogen. After overnight stirring, release the hydrogen, remove the catalyst by filtration, and wash the catalyst by 1,2-dichloroethane several times. Concentrate down to a residue, which purified by flash chromatography on silica gel, gradient (100% hexane to 100% of Hexane:CH₂Cl₂:EtOAc=50:50:2.5), afford brownish solid 3.6 g of title compound (yield 73%). Mass spectrum: ES(+)(m/e): 175 (M+1); ¹H NMR (300MHz, DMSO-d6, ppm): δ 7.81 (br, 2H), 7.65–7.62 (m, 1H), 7.28–7.24 (m, 2H), 7.11–7.01 (m, 1 H).

Example 531 2-(5-Fluoro-2-nitro-phenylamino)-benzo[b]thiiophene-3-carbonitrile

Combine 2-amino-benzo[b]thiophene-3-carbonitrile (2.25 g, 12.5 mmol), 2,4-difluoro-nitrobenzene (1.99 g, 12.5 mmol and Lithium hydroxide (0.58 g, 25 mmol) ) in 30 mL of DMSO and heat to 50 ° C., after 4 hours, cool the reaction to the RT, and pour on ice, stir for 30 min, extract with CH₂Cl₂, the combined solvent wash with water and brine, dry over Na₂SO₄. Concentrate down to a residue treat with MeOH, the orange precipitate collect by suction filtration give title compound, 2.15 g. Concentrate the filtrate and purify by flash chromatography to give 0.22 g orange solid. Total 2.35 g, yield 61%. Mass spectrum: ES(+) (m/e): 314 ((M+1): ¹H NMR (300 MHz, DMSO-d6) δ: 10.35 (br, 1H), 8.31–8.25 (m, 1H), 8.00–7.96 (m, 1H), 7.68–7.65 (m, 1H), 7.53–7.37 (m, 3H), 7.13–7.07 9 m, 1H); ¹³CNMR (75 MHz, DMSO-d6) δ ppm: 165.5 (d, J=254.5 Hz), 156.2, 139.8 (d, J=12.5 Hz), 135.9, 134.8, 132.2, 129.3 (d, J=11.7 Hz), 126.3, 125.2, 123.0, 120.4, 113.5, 110.4 (d, J=24.0 Hz), 107.6 (d, J=27.4 Hz), 92.9.

Example 532 9-Fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine, hydrochloride

Combine 2-(5-fluoro-2-nitro-phenylamino)-benzo[b]thiiophene-3-carbonitrile (2.15 g, 6.87 mmol) and Tin(II) chloride, dihydrate (4.65 g, 20.6 mmol) in a mixed solvent of EtOH (25 mL) and 5.0 N HCl (25 mL), heat the suspension to reflux for 3 hours, cool to RT. The title compound 1.73 g (yield 78%) is obtained as a yellow solid by suction filtration. Mass spectrum: ACPI (m/e): 284 ((M+1-HCl); ¹H NMR (300 MHz, DMSO-d6) δ 11.46 (br, 1H), 10.02 (br, 1H), 9.02 (br, 2H), 7.90–7.87 (m, 1H), 7.71–7.68 (m, 1H), 7.46–7.40 (m, 1H), 7.33–7.28 (m, 1H), 7.12–6.94 (m, 2H), 6.85–6.81 (m, 1H).

Example 533 (S)-9-Fluoro-5-[3-phenethyl-piperazine-1-yl]-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Combine 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrogen chloride (287 mg, 0.9 mmol), (S)-2-phenethyl-piperazine (340 mg, 1.80 mmol) and diisopropylethyl amine (116 mg, 0.9 mmol) in DMSO (0.5 mL) and toluene (2.0 mL), stir and microwave (300 W, 125 ° C.) for 8 h, then heat to 115 ° C. for 22 h. Cool the reaction to RT, dilute with CH₂Cl₂, wash with H₂O and brine. Dry the organic layer with by Na₂SO₄. The crude material purify by chromatography on silica gel, gradient (100% CH₂Cl₂ to 100% CH₂Cl₂:2N NH₃/MeOH=25:1), give 137 mg of title compound.

Example 534 (S)-9-Fluoro-5-[3-phenethyl-4-methyl-piperazine-1-yl]-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene, dihydrochloride

By using a method similar to the method of Example 492, using (S)-9-fluoro-5-[3-phenethyl-piperazine-1-yl]-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene, (92 mg, 0.2 mmol), formaldehyde (37%, w/w, aq) (20 mg, 0.25 mmol) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) in 3 mL 1,2-dichloroethane and stir at RT. After purification, give 82 mg of free base. Mass spectrum: ACPI (m/e): 471.10 ((M+1-HCl) The dihydrochloric salt is form by adding 5 eq of acetyl chloride (68.4 mg, 0.89 mmol) to the free base (82 mg, 0.17 mmol) in ethanol (5 mL). After removing the solvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 81 mg of title compound as yellow solid.

Example 535 (S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Add 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.66 g, 2.1 mmol) to a solution of (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.91 g, 4.1 mmol) in dimethyl sulfoxide: toluene (1:8, 9 mL). Add diisopropylethylamine (0.36 mL, 2.1 mmol), heat to 110° C., and stir. After 51 hours, cool to ambient temperature, and dilute with ethyl acetate and 0.1 N NaOH. Separate the aqueous layer and extract it with ethyl acetate (2×). Wash all organics with a saturated solution of sodium chloride, and then dry (sodium sulfate), filter, and concentrate them under reduced pressure to an oil (1.27 g). Purify the oil by flash chromatography, eluting with a gradient of a 3% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane). Reconstitute the material in ethyl acetate and wash it with a saturated solution of sodium chloride (2×) to remove residual dimethylsulfoxide. Back extract the combined aqueous layers with ethyl acetate. Dry (sodium sulfate) the organic phases, filter, and concentrate them under reduced pressure to give the title compound (0.389 g): mass spectrum (APCI+, m/e): 487 (M+1).

Example 536 (S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene dihydrochloride

Using a method similar to the method Example 513, using (S)-9-fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.070 g, 0.14 mmol) and a solution of acetyl chloride (0.052 mL, 0.72 mmol) in absolute ethanol at ambient temperature gives the title compound (0.76 g): mass spectrum (APCI+, m/e): 487 (M+1–2HCl); exact mass spectrum (ES+, m/e, C₂₈H₂₇FN₄OS.2HCl): calc. 487.1968 (M+1–2HCl), found 487.1972.

Example 537 (S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene

Using a method similar to the method of Example 535, using 9-fluoro-11H-12-thia-6, 11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.62 g, 1.9 mmol) and (S)-2-[2-(3-methoxy-phenyl)-ethyl]-piperazine (0.85 g, 3.9 mmol), and purifying by flash chromatography, eluting with a solution of 2% 2M ammonia in methanol, in dichloromethane (33–66% in dichloromethane over 7 minutes, 66–100% over 28 minutes, 100% for 23 minutes) gives the title compound (0.251 g): mass spectrum (APCI+, m/e): 487 (M+1).

Example 538 (S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene dihydrochloride

Using a method similar to the method of 513, using (S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.070 g, 0.14 mmol) and a solution of acetyl chloride (0.0514 mL, 0.720 mmol) in absolute ethanol at ambient temperature gives the title compound (0.081 g). Exact mass spectrum (ES+, m/e, C₂₈H₂₇FN₄OS.2HCl): calc. 487.1968 (M+1–2HCl), found 487.1973.

Example 539 (S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene

Using a method similar to the method of Example 535, using 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.66 g, 2.1 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.86 g, 4.1 mmol), stirring at 110 ° C. for 24 hours, and purifying by flash chromatography, eluting with a solution of 3% 2M ammonia in methanol, in dichloromethane (33–66% in dichloromethane over 15 minutes, 66–100% over 30 minutes, 100% for 13 minutes) gives the title compound (0.307 g). Mass spectrum (APCI+, m/e): 475 (M+1).

Example 540 (S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene dihydrochloride

Using a method similar to the method 513, using (S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.055 g, 0.12 mmol) and a solution of acetyl chloride (0.041 mL, 0.58 mmol) in absolute ethanol at ambient temperature gives the title compound (0.062 g). Mass spectrum (APCI+, m/e): 475 (M+1–2HCl); exact mass spectrum (ES+, m/e, C₂₇H₂₄F₂N₄.S2HCl): calc. 475.1768 (M+1–2HCl), found 475.1781.

Example 541 (S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene

Using a method similar to the method of Example 535, using 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.66 g, 2.1 mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.86 g, 4.1 mmol), and stirring at 110 ° C. for 47.5 hours gives the title compound (0.426 g). Mass spectrum (APCI+, m/e): 475 (M+1).

Example 542 (S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene dihydrochloride

Using a method similar to the method 513, using (S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.062 g, 0.13 mmol) and a solution of acetyl chloride (0.047 mL, 0.66 mmol) in absolute ethanol at ambient temperature gives the title compound (0.072 g). Mass spectrum (APCI+, m/e): 475 (M+1–2HCl); exact mass spectrum (ES+, m/e, C₂₇H₂₄F₂N₄S.2HCl): calc. 475.1768 (M+1–2HCl), found 475.1787.

Example 543

(S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Add sodium triacetoxyborohydride (0. 183 g, 0.863 mmol) and aqueous formaldehyde (37% w/w, 0.065 mL, 0.86 mmol) to a solution of(S)-9-fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.28 g, 0.58 mmol) in dichloroethane and stir. After 2 hours, dilute with a saturated aqueous solution of sodium bicarbonate and dichloromethane, and separate the layers. Extract the aqueous layer with dichloromethane. (2×), combine organics, and wash them with a saturated solution of sodium chloride. Dry (sodium sulfate) the organics, filter, and concentrate them under reduced pressure to a residue (0.38 g). Purify the residue by flash chromatography, eluting with a gradient of a solution of ethyl acetate: hexane (3:2) with 1% 2M ammonia in methanol added (in hexane) to give the title compound: (0.214 g, 74%). Mass spectrum (APCI+, m/e): 501 (M+1).

Example 544 (S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene dihydrochloride

Add a solution of acetyl chloride (0.144 mL, 2.02 mmol) in absolute ethanol to a solution of (S)-9-fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.174 g, 0.348 mmol) in absolute ethanol and stir briefly at ambient temperature. Concentrate solution under reduced pressure to give an orange solid. Reconstitute the solid in acetonitrile: water (1:1), freeze-dry the solution in a dry-ice/acetone bath, and lyophilize overnight to give the title compound (0.208 g) as a yellow solid: mass spectrum (APCI+, m/e): 501 (M+1–2HCl); exact mass spectrum (ES+, m/e, C₂₉H₂₉FN₄OS.2HCl): calc. 501.2124 (M+1–2HCl), found 501.2130.

Example 545 (S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Using a method similar to the method of Example 543, using (S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.164 g, 0.337 mmol), sodium triacetoxyborohydride (0.107 g, 0.505 mmol), and aqueous formaldehyde (0.038 mL, 0.50 mmol) in dichloroethane gives the title compound (0.136 g): mass spectrum (APCI+, m/e): 501 (M+1).

Example 546 (S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-11-thia-6,11-diaza-dibenzo[a,f]azulene dihydrochloride

Using a method similar to the method of Example 544, using (S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.110 g, 0.220 mmol) and a solution of acetyl chloride (0.0784 mL, 1.10 mmol) in absolute ethanol at ambient temperature gives the title compound (0.123 g). Mass spectrum (APCI+, m/e): 501 (M+1–2HCl); exact mass spectrum (ES+, m/e, C₂₉H₂₉FN₄OS.2HCl): calc. 501.2124 (M+1–2HCl), found 501.2136.

Example 547 (S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Using a method similar to Example 543, using (S)-9-fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-1H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.218 g, 0.459 mmol), sodium triacetoxyborohydride (0.146 g, 0.689 mmol), and aqueous formaldehyde (0.052 mL, 0.69 mmol) in dichloroethane gives the title compound (0.185 g). Mass spectrum (APCI+, m/e): 489 (M+1).

Example 548 (S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene dihydrochloride

Using a method similar to the method of Example 544, using (S)-9-fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.144 g, 0.294 mmol) and a solution of acetyl chloride (0.105 mL, 1.47 mmol) in absolute ethanol at ambient temperature gives the title compound (0.179 g). Mass spectrum (APCI+, m/e): 489 (M+1–2HCl); exact mass spectrum (ES+, m/e, C₂₈H₂₆F₂N₄S.2HCl): calc. 489.1924 (M+1–2HCl), found 489.1918.

Example 549 (S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Using a method similar to the method of Example 543, using (S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.339 g, 0.714 mmol), sodium triacetoxyborohydride (0.227 g, 1.07 mmol), and aqueous formaldehyde (0.080 mL, 1.1 mmol) in dichloroethane, and employing a second chromatographic purification, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 2% 2M ammonia in methanol (in hexane) added, gives the title compound (0.238 g). Mass spectrum (APCI+, m/e): 489 (M+1).

Example 550 (S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene dihydrochloride

Using a method similar to the method of Example 544, using (S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.206 g, 0.422 mmol) and a solution of acetyl chloride (0.151 mL, 2.12 mmol) in absolute ethanol at ambient temperature gives the title compound (0.228 g): mass spectrum (APCI+, m/e): 489 (M+1–2HCl); exact mass spectrum (ES+, m/e, C₂₈H₂₆F₂N₄S.2HCl): calc. 489.1924 (M+1–2HCl), found 489.1918.

Example 551 2-(2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile

By using a method similar to the method of Example 490, combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.56 g, 20.5 mmol), 2-fluoro-nitrobenzene (2.88 g, 20.5 mmol) and Lithium hydroxide (0.96 g, 41.0 mmol) ) in 50 mL of DMSO and heat to 50 ° C., after over night heating to give 5.0 g, yield 83%. Mass spectrum: ES(+) (m/e): 296.0 ((M+1); ¹H NMR (400 MHz, DMSO-d6) ppm: 10.27 (s, 1H), 8.13 (dd, 1H, J=1.7 Hz, J=8.3 Hz), 7.91–7.89 (m, 1H), 7.76–7.72 (m, 1H), 7.64–7.57 (m, 2 H), 7.48–7.44 (m, 1H), 7.36–7.32 (m, 2H).

Example 552 11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride

By using a method similar to the method of Example 532, combine 2-(2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (5.0 g, 17.0 mmol) and Tin(II) chloride (9.65 g, 51.0 mmol) in a mixed solvent of EtOH (50 mL) and 5.0 N HCl (50 mL), heat the suspension to reflux for 3 hours, cool to RT. The title compound 4.65 g (yield 91%) is obtained as a yellow solid by suction filtration. Mass spectrum: ACPI (m/e): 266.0 ((M+1-HCl); ¹H NMR (300 MHz, DMSO-d6) ppm: 11.7 (br, 1H), 10.00 (br, 1H), 9.10 (br, 2H), 7.90–7.85 (m, 1H), 7.72–7.65 (m, 1H), 7.48–7.38 (m, 1H), 7.35–7.28 (m, 1H), 7.22–6.98 (m, 4H).

Example 553 2-(2-Nitro-phenylamino)-benzonitrile

Combine 1-fluoro-2-nitro-benzene (5.00 g, 35.44 mmol), 2-amino-benzonitrile (4.19 g, 35.44 mmol), lithium hydroxide monohydrate (2.97 g, 70.87 mmol) and DMSO (50.0 ml). Stir the mixture at 55 ° C. for 19 hours then cool to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dry the precipitate under vacuum to give 6.14 g (72%) of an orange solid: mp 134–138°.

Example 554 5H-Dibenzo[b,e][1.4]diazepin-11-ylamine hydrochloride

Combine 2-(2-Nitro-phenylamino)-benzonitrile (6.14 g, 25.66 mmol), tin(II) chloride dihydrate (17.37 g, 76.99 mmol), 5N HCl (105 ml), and ethanol (65.0 ml). Stir the mixture at reflux for 24 hours then cool it to ambient temperature and chill it in the refrigerator for 2 hours. Remove the ethanol under vacuum and chill in the refrigerator again. Filter off the resulting precipitate by vacuum filtration and dry it in a vacuum oven to give 6.31 g (100%) of a yellow solid: mass spectrum (ion spray): m/z=210.0 (M+1).

Example 555 2-Amino-5-isopropyl-benzonitrile

Combine 2-bromo-4-isopropyl aniline (7.5 g, 35 mmol) and copper (I) cyanide (3.76 g, 42 mmol) in NMP (30.0 mL) and heat at 200° C. for 2 hours. Cool to ambient temperature and dilute with water (300 mL). Extract with ethyl acetate to give 4.58 g of the crude product. Silica gel chromatography, eluting with methylene chloride, gives 3.20 g of the title compound as a red oil: mass spectrum (ion spray): m/z=161 (M+1); ¹H NMR (300 MHz, DMSO-d₆): δ 7.21 (m, 2H), 6.73 (d, 1H), 5.79 (s, 2H), 2.73 (quintet, 1H), 1.12 (d, 6H).

Example 556 5-Isopropyl-2-(2-nitro-phenylamino)-benzonitrile

Combine 2-amino-5-isopropyl-benzonitrile (3.19 g, 20 mmol), 1-fluoro-2-nitro benzene (2.1 mL, 20 mmol) and lithium hydroxide (1.68 g, 40 mmol) in DMSO (40.0 mL) and heat at 55° C. for 19 hours. Cool to ambient temperature and dilute with water (200 mL). The title compound precipitates as 4.56 g of an orange solid: mp 91–96° C.; mass spectrum (ion spray) m/z=280 (M+1).

Example 557 2-Isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride

Combine 5-isopropyl-2-(2-nitro-phenylamino)-benzonitrile (4.54 g, 16.1 mmol) and tin (II) chloride (10.92 g, 48.4 mmol) in 65.0 mL of 5N HCl solution and 65.0 mL of ethanol. Heat this mixture at 86° C. for 18 hours. Chilling the mixture precipitates the title compound as 4.22 g of a yellow solid: mp>250° C.; mass spectrum (ion spray): m/z=252 (M+1).

Example 558 2-Amino-5-isopropyl-benzonitrile

Heat a mixture of copper (I) cyanide (2.5 g, 28.02 mmol), and 2-bromo4-isopropyl-phenylamine (5.0 g, 23.35 mmol) in 1-methyl-2-pyrrolidinone (20 ml) to 195° C. for four hours. Dilute the reaction mixture with 100 ml of ethyl acetate and wash the dark solution twice with 28% aqueous ammonium hydroxide, twice with saturated aqueous sodium chloride (brine) and twice with water. Collect the organic layer, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue via flash chromatography eluting with a step gradient starting with hexanes and going to 80% hexanes with 20% ethyl acetate to obtain 3.31 g (20.66 mmol, 88% yield) of the title compound as an orange oil: Mass Spectrum (m/e): 161(M+1).

Example 559 2-(4-Fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile

Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.482 g, 9.25 mmol) with 1,4-difluoro-2-nitro-benzene (1.47 g, 9.25 mmol) and lithium hydroxide monohydrate (0.78 g, 18.50 mmol) in DMSO (20 ml) to 70° C. for 38 hours. Cool the reaction to ambient temperature and then pour into approximately 200 ml of ice water and stir for one hour. The title compound precipitates and collection by filtration to obtain 2.236 g (7.47 mmol, 81% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 300(M+1).

Example 560 8-Fluoro-2-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride

By using a method similar to the method of Example 532, using 2-(4-fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.559 g, (1.87 mmol), tin (II) chloride(1.06 g, 5.60 mmol) to obtain (0.422 g, 1.38 mmol, 74% yield) of the title compound as a yellow amorphous solid: Mass Spectrum (m/e): 270(M+1).

Example 561 2-(4-Fluoro-2-nitro-phenylamino)-5-methyl-benzonitrile

Combine 4-fluoro-2-nitro-phenylamine (2.9 g, 18.50 mmol), 2-fluoro-5-methyl-benzonitrile (2.5 g, 18.50 mmol) and lithium hydroxide monohydrate (2.4 g, 57.20 mmol) in methyl sulfoxide (DMSO, 40 ml). Heat the resulting mixture to 55° C. for 40 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate. Chromatograph the solid using flash chromatography and elute with mobile phase: 90% hexanes, 5% ethyl acetate, and 5% dichloromethane. Obtained 2.267 g of the title compound (8.36 mmol, 45% yield) as an orange amorphous solid.

Mass Spectrum (m/e): 272(M+1).

Example 562 8-Fluoro-2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride

Heat a solution of 2-(⁴-fluoro-2-nitro-phenylamino)-5-methyl-benzonitrile (1.747 g, 6.44 mmol) in ethanol (35 ml) to 60° C. and add a solution of tin (II) chloride (6.06 g, 31.96 mmol) in 5.0 N hydrochloric acid (35 ml). Reflux the resulting mixture to reflux for 40 hours. Cool the reaction to room temperature and place in a freezer for 16 hours. The product precipitates from the solution and is collected by filtration to obtain 1.3 g of the title compound (4.68 mmol, 73% yield) as a yellow-green amorphous solid: Mass Spectrum (m/e): 241 (M+1).

Example 563 4-methyl-2-(2-nitro-phenylamino)-benzonitrile

Combine 1-fluoro-2-nitro-benzene (5.34 g, 37.83 mmol), 2-amino-4-methyl-benzonitrile (5.00 g, 37.83 mmol), lithium hydroxide monohydrate (3.17 g, 75.66 mmol) and DMSO (70.0 ml). Stir the mixture at 55° C. for 16 hours then cool it to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting yellow precipitate by vacuum filtration. Dry the precipitate under vacuum then recrystallize it in ethanol to give 5.15 g (54%) of fine, amber colored needles: mp 162–164°; mass spectrum (ion spray): m/z=254.0 (M+1).

Example 564 5-methyl-2-(2-nitro-phenylamino)-benzonitrile

Combine 1-fluoro-2-nitro-benzene (4.34 g, 30.79 mmol), 2-amino-5-methyl-benzonitrile (4.07 g, 30.79 mmol), lithium hydroxide monohydrate (2.58 g, 61.58 mmol) and DMSO (50.0 ml). Stir the mixture at 55° C. for 22 hours then cool it to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dry the precipitate under vacuum then purify it on silica gel using dichloromethane/hexanes (75:25) to give 4.45 g (57%) of an orange solid: mp 135–139°; mass spectrum (ion spray): m/z=254.0 (M+1).

Example 565 2-Amino-5-methyl-benzonitrile

Combine 2-bromo-4-methyl-phenylamine (8.00 g, 43.0 mmol), CuCN (4.62 g, 51.6 mmol), and NMP (30.0 ml). Stir the mixture at reflux for 75 minutes then cool it to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dissolve the precipitate in NH₄OH and extract it with dichloromethane. Combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/hexanes (75:25) to give 3.39 g (60%) of an orange solid: mass spectrum (ion spray): m/z=133.1 (M+1).

Example 566 2-Methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride

Combine 5-methyl-2-(2-nitro-phenylamino)-benzonitrile (4.03 g, 15.91 mmol), tin(II) chloride dihydrate (10.77 g, 47.74 mmol), 5N HCl (65 ml), and ethanol (40.0 ml). Stir the mixture at reflux for 7 hours then cool it to ambient temperature and chill it in the refrigerator overnight. Remove the resulting precipitate by vacuum filtration. Place the precipitate in ethanol (100.0 ml) and 5N HCl (20.0 ml) and heat at reflux for 19 hours. Cool the reaction mixture to ambient temperature then chill it in the refrigerator. Filter off the resulting precipitate by vacuum filtration and dry it in a vacuum oven to give 2.59 g (63%) of an orange solid: mass spectrum (ion spray): m/z=224.0 (M+1).

Example 567 3-Methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride

Combine 4-methyl-2-(2-nitro-phenylamino)-benzonitrile (2.46 g, 9.71 mmol), tin(II) chloride dihydrate (6.57 g, 29.71 mmol), 5N. HCl (40 ml), and ethanol (40.0 ml). Stir the mixture at reflux for 8 hours then cool it to ambient temperature. Allow the mixture to stand at ambient temperature overnight then chill it for 3 hours in the refrigerator. Remove the resulting precipitate by vacuum filtration and dry it under vacuum to give 1.24 g (49%) of the desired compound as a yellow solid: mass spectrum (ion spray): m/z=224.0 (M+1).

Example 568 (S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-5H-dibenzo[b,e][1,4]diazepine succinate

Heat a solution of 8-fluoro-2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.391 g, 1.62 mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.68 g, 3.24 mmol) in 1-methyl-2-pyrrolidinone (8mL) to 195° C. for 14 hours. Cool reaction mixture to ambient temperature. Dilute with 100 ml of ethyl acetate and wash twice with brine, twice with water, and once again with brine. Collect the organic layer and dry over sodium sulfate. Remove solvent under reduced pressure. Purification via flash chromatography, eluting with a step gradient starting with 100% of a stock mixture of 75% ethyl acetate with 25% dichloromethane and going to 90% of the stock mixture with 10% 2M ammonia in methanol, gives the free base of the title compound (0.108 g, 0.25 mmol, 15% yield) as a yellow amorphous solid. Convert the product to the succinate salt by dissolving the product in methanol and adding one equivalent of succinic acid, swirl or sonicate the mixture until no solid succinic acid remains, then removing the solvent under reduced pressure gives the title compound: Mass Spectrum (m/e): 433(M+1).

Example 569 (S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-5H-dibenzo[b,e][1,41]diazepine succinate

Dissolve (S)-8-fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-5H-dibenzo[b,e][1,4]diazepine (0.076 g, 0.18 mmol) in dichloromethane (10 ml). Add sodium triacetoxyborohydride (0.112 g, 0.53 mmol) and formaldehyde (0.011 g, 0.35 mmol, 0.029 g of a 37% aqueous solution) and stir the mixture for one hour at ambient temperature. Dilute the mixture with brine and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and remove the solvent under reduced pressure. Purification via flash chromatography, eluting with a step gradient starting with 100% of a stock mixture of 70% hexanes with 30% dichloromethane and going to 90% of the stock mixture with 10% 2M ammonia in methanol, gives the free base of the title compound (0.028 g, 0.06 mmol, 36% yield) as a yellow foam. Convert to to the succinate salt as described previously: Mass Spectrum (m/e): 446(M+1).

Example 570 (S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine succinate

Heat a solution of 8-fluoro-2-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.308 g, 1.01 mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.629 g, 3.02 mmol) in 1-methyl-2-pyrrolidinone (8 mL) to 195° C. for 14 hours. Cool reaction mixture to ambient temperature. Dilute with 50 ml of ethyl acetate and wash twice with brine, twice with water, and once again with brine. Collect the organic layer and dry over sodium sulfate. Remove solvent under reduced pressure. Purification via flash chromatography, eluting with a step gradient starting with 100% of a stock mixture of 80% ethyl acetate with 20% dichloromethane and going to 95% of the stock mixture with 5% 2M ammonia in methanol, gives the free base of the title compound (0.132 g, 0.29 mmol, 28% yield) as a yellow amorphous solid. Convert to the succinate salt as described previously: Mass Spectrum (m/e): 461(M+1).

Example 571 (S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine succinate

Dissolve (S)-8-fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine (0.066 g, 0.14 mmol) in dichloromethane (8 ml). Add sodium triacetoxyborohydride (0.091 g, 0.43 mmol) and formaldehyde (0.009 g, 0.29 mmol, 0.023 g of a 37% aqueous solution) and stir the mixture for one hour at ambient temperature. Dilute the mixture with brine and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and remove the solvent under reduced pressure. Purification via flash chromatography, eluting with a step gradient starting with 100% of a stock mixture of 70% hexanes with 30% dichloromethane and going to 90% of the stock mixture with 10% 2M ammonia in methanol, gives the free base of the title compound (0.032 g, 0.07 mmol, 47% yield) as a yellow foam. Convert to the succinate salt as described previously: Mass Spectrum (m/e): 475(M+1).

Example 572 (S)-11-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine

Combine 2-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine (0.665 g, 2.31 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.962 g, 4.62 mmol)in toluene (4.0 mL) and DMSO (1.0 mL) and heat at 110° C. for 18 hours. Cool to ambient temperature and dilute with ethyl acetate (75 mL). Wash with 0.1N NaOH solution, water and evaporate to give 0.996 g of the crude product. Silica gel chromatography, eluting with methylene chloride: 2N NH₃/methanol (100:4), gives 0.216 g of the title compound as a tan solid: mass spectrum (ion spray): n/z=443 (M+1).

Example 573 (S)-11-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine dihydrochloride

In a manner such as that described in Example 461, using (S)-11-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine (0.351 g, 0.79 mmol) gives 0.176 g of the title compound as an orange solid: mp 227° C.; mass spectrum (ion spray): m/z=457 (M+1); Analysis for C₂₉H₃₅Cl₂FN₄(0.2H₂O): calcd: C, 65.33; H, 6.69; N, 10.51; found: C, 65.22; H, 6.70; N, 10.39.

Example 574 3-Methyl-11-(4-methyl-piperazin-1-yl)-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (636.4 mg, 2.85 mmol), N-methylpiperazine (444.2 mg, 3.08 mmol), N,N-diisopropylethylamine (856.5 mg, 8.55 mmol), DMSO (2.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 110° C. After 48 hours, add one drop of 5N HCl. After 72 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with DI H₂O and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 362.9 mg (42%) of a tan foam: mp 84°, dec; mass spectrum (ion spray): m/z=307.1 (M+1).

Example 575 3-Methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (400.0 mg, 1.54 mmol), (S)-2-phenethyl-piperazine (879.1 mg, 4.62 mmol), N,N-diisopropylethylamine (199.0 mg, 1.54 mmol), DMSO (0.7 ml), and toluene (2.8 ml). Stir and heat the mixture at 110° C. After 65 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 518.7 mg (85%) of a tan foam: mp 64°–80°; mass spectrum (ion spray): m/z=397.2 (M+1).

Example 576 3-Methyl-11-[4-methyl-(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine 3-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (375.0 mg, 0.95 mmol), formaldehyde (84.4 μL, 1.04 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (300.6 mg, 1.42 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 329.5 mg (85%) of the title compound as a tan foam: mp 65°, dec; mass spectrum (ion spray): m/z=411.3 (M+1).

Example 577 11-{(S)-3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-1-ylamine hydrochloride (400.0 mg, 1.54 mmol), (S)-2-[2-(3-Fluoro-phenyl)-ethyl]-piperazine (641.5 mg, 3.08 mmol), N,N-diisopropylethylamine (199.0 mg, 1.54 mmol), DMSO (0.7 ml), and toluene (2.8 ml). Stir and heat the mixture at 110° C. After 64 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 423.2 mg (66%) of a tan foam: mp 81°, dec; mass spectrum (ion spray): m/z 415.2 (M+1).

Example 578 11-{(S)-3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine 11-{(S)-3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine (385.5 mg, 0.93 mmol), formaldehyde (83.0 μL, 1.02 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (295.6 mg, 1.39 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 366.2 mg (92%) of the title compound as a yellow foam: mp 63°, dec; mass spectrum (ion spray): m/z=429.3 (M+1).

Example 579 2-Methyl-11-(4-methyl-piperazin-1-yl)-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine 2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg, 2.31 mmol), N-methylpiperazine (1.39 g, 13.86 mmol), N,N-diisopropylethylamine (298.6 mg, 2.31 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 110° C. After 48 hours, cool the mixture to ambient temperature and stir it overnight. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 550.5 mg (78%) of a tan foam: mp 170°–177°, dec; mass spectrum (ion spray): m/z=307.2 (M+1).

Example 580 2-Methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine 2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg, 2.31 mmol), (S)-2-phenethyl-piperazine (879.1 mg, 4.62 mmol), N,N-diisopropylethylamine (298.6 mg, 2.31 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 110° C. After 67 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 646.3 mg (71%) of a tan foam: mp 67°, dec; mass spectrum (ion spray): m/z=397.3 (M+1).

Example 581 2-Methyl-11-[4-methyl-(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine 2-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (300.0 mg, 0.76 mmol), formaldehyde (67.5 μL, 0.83 mmol, 37% in water), and 1,2-dichloroethane (25.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (240.5 mg, 1.13 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 279.7 mg (90%) of the title compound as a yellow foam: mp 65°, dec; mass spectrum (ion spray): m/z=411.2 (M+1).

Example 582 11-(4-Methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

Combine 5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg, 2.44 mmol), N-methylpiperazine (1.47 g, 14.65 mmol), N,N-diisopropylethylamine (315.6 mg, 2.44 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and beat the mixture at 110° C. After 21 hours, cool the mixture to ambient temperature and stir it overnight. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 319.7 mg (45%) of a tan foam: mp 173° C. –179° C., dec; mass spectrum (ion spray): m/z=293.1 (M+1).

Example 583 2-(4-Chloro-2-nitro-phenylamino)-benzonitrile

Combine anthranilonitrile (2.36 g, 20 mmol), sodium hydride (1.2 g (60% in oil), 30 mmol) and THF (50 mL), stir at ambient temperature for 30 minutes. Add 1-bromo4-chloro-2-nitro-benzene (7.1 g, 30 mmol) and stir at ambient temperature for 3 days. Pour the reaction mixture in ice-cold concentrated hydrochloric acid (200 mL) and filter the resulting solid. Purify by flash chromatography (dichloromethane) and recrystallize from hot ethyl acetate to give (1.62 g, 30%) of the title compound as orange needles: ¹H NMR (CDCl₃) δ 7.17 (d, 1H), 7.26 (t, 1H), 7.40–7.51 (m, 2H), 7.61 (t, 1H), 7.72 (d, 1H), 8.22 (d, 1H), 9.54 (bs, 1H).

Example 584 8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride

Combine 2-(4-chloro-2-nitro-phenylamino)-benzonitrile (1.2 g, 4.4 mmol) in ethanol (40 mL) with a solution of stannous chloride dihydrate (2.9 g, 13.2 mmol) in 12 N hydrochloric acid (13 mL). Stir and reflux for 2 hours, cool to ambient temperature and concentrate. Add water (200 mL), filter and dry to give (890 mg, 72%) of the title compound as a yellow solid: ¹H NMR (DMSO-d₆) δ 6.84–6.69 (m, 5E), 7.27–7.17 (m, 2H), 8.02 (s, 1H), 8.83 (bs, 1H), 9.36 (bs, 1H); MS (APCI) m/z (rel intensity) 244.3 (100).

Example 585 11-(3-(S)-Benzyl-piperazin-1-yl)-8-chloro-5H-dibenzo[b,e][1,4]diazepine

Combine 3-(S)-benzyl-piperazine (800 mg, 4.5 mmol), 8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (424 mg, 1.5 mmol), toluene (8 mL), dimethylsulfoxide (2 mL) and reflux for 3 days. Concentrate and pour into water (50 mL), filtrate the resulting solid, redissolve in dichloromethane (200 mL), wash with water and dry over magnesium sulfate. After concentration, purify by flash chromatography (dichloromethane then gradient of methanol 3–10%) to give (316 mg, 53%) of the title compound as a yellow foam: mp 79–92° C.; ¹H NMR (CDCl₃): δ 2.59 (dd, 1H), 2.90–2.66 (m, 3H), 3.09–2.94 (m, 3H), 3.85 (bm, 1H), 4.03 (bm, 1H), 4.88 (s, 1H), 6.61 (dd, 1H), 6.79–6.84 (m, 2H), 6.97 (t, 1H), 7.06 (t, 1H), 7.35–7.19 (m, 7H); MS (APCI) m/z (rel intensity) 403.4 (100).

By a method similar to Example 585, using 8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride, the following compound was prepared and isolated as the (S) isomer.

No: ArAlk Data 586 CH₂CH₂Ph mp 78–92° C.; ¹H NMR(CDCl₃): δ1.76–1.64(m, 2H), 2.74–2.54(m, 4H), 3.07–2.78(m, 4H), 3.84(bm, 1H), 4.00(bm, 1H), 4.88(s, 1H), 6.61(dd, 1H), 6.83–6.80(m, 2H), 7.08–6.99(m, 2H), 7.32–7.15(m, 7H); MS(APCI)m/z(rel intensity) 417.4(100). 49% yield.

By a similar method to Example 90, the following compounds were prepared and isolated, using 8-Chloro-5H-dibenzo(b,e)(1,4)diazepin-11-ylamine hydrochloride, as the (S) isomer.

No: ArAlk Data 587 CH₂CH₂Ph mp 64–78° C.; ¹H NMR(CDCl₃): δ1.80–1.69(m, 1H), 2.00–1.89(m, 1H), 2.28–2.19(m, 1H), 2.35(s, 3H), 2.44–2.34(m, 1H), 2.59–2.48(m, 1H), 2.75–2.64(m, 1H), 2.85(d, 1H), 2.93(t, 1H), 3.22–3.10(m, 1H), 3.80(bm, 1H), 3.93(bm, 1H), 4.87(s, 1H), 6.61(d, 1H), 6.82(dd, 2H), 7.01(dt, 1H), 7.08(d, 1H), 7.21–7.14(m, 3H), 7.33–7.24(m, 4H); MS(APCI)m/z(rel intensity) 431.3(90), 270.4(100). 83% yield. 588 CH₂Ph mp 69–81° C.; ¹H NMR(CDCl₃): δ2.50–2.39(m, 3H), 2.48(s, 3H), 2.94–2.71(m, 2H), 3.24–3.10(m, 2H), 3.51(bm, 1H), 3.85(bm, 1H), 4.83(s, 1H), 6.57(dd, 1H), 6.81–6.71(m, 3H), 6.97(s, 1H), 7.25–7.02(m, 7H); MS(APCI)m/z(rel intensity)417.3(100). 96% yield.

Example 589 5-Amino-4-carboxamido-1H-1,2,3-triazole

Dissolve 4-toluenesulphonyl chloride (481.3 g; 2.52 mol) in hot ethanol (2900 ml) and allow the resulting clear solution to cool to room temperature. Dissolve sodium azide (198.31 g; 3.05 mol) in water (360 ml) and mix the two solutions with stirring. Allow the mixture to stand for one and a half hours at room temperature, pour onto water (7250 ml) and separate the resulting two phase mixture, wash the clear oil with water, dry over magnesium sulphate and filter to leave the desired 4-toluene sulphonyl azide (weight=470.57 g).

Add to the Chem Reactor sodium methoxide in methanol (25% by weight; 470 ml) and further methanol (470 ml). Add malonamidine hydrochloride (300 g; 2.18 mol) to the solution with stirring. Stir the white slurry formed for half an hour under nitrogen, cool to 0–5° C. using an ice-water bath. Add at this temperature, ethanol (3600 ml) and stir the mixture stir for one hour at 10° C. Filter the mixture to remove sodium chloride and wash the latter with further ethanol (1000 ml). Place the resultant amidine solution back in the Chem Reactor and cool to 5° C. Add the solution of 4-toluenesulphonyl azide (470.57 g) in ethanol (380 ml) add dropwise over 30 minutes. Stir the mixture at room temperature overnight, filter and wash with ethanol to leave a white solid, dry at 60° C. in a vacuum oven to give 5-amino4-carboxamido-1H-1,2,3-triazole=245.6 g (88.6% yield).

Example 590 5-Amino-2-isopropyl-2H-1,2,3-triazole-4-carboxamide

Combine 5-amino-4-carboxamido-1H-1,2,3-triazole (127 g, 1.0 mol) and 2-bromopropane (160 g, 1.3 mol) in toluene (1500 ml) and stir at 70° C. for eighteen hours in the presence of 50% aqueous sodium hydroxide (2.0 ml) and potassium carbonate (276 g; 2.0 mol) with Adogen 464 (25 g) as the phase transfer catalyst. After cooling water add and extract the product using ethyl acetate. Wash the combined organic phases with water, dry over magnesium sulphate and remove the solvent in vacuo to leave a residue that is triturated with diethyl ether. Collect the white solid by filtration and dry under vacuum at room temperature to give 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carboxamide (94.68 g, 56% yield). Alkylation occurs at other positions including the exocyclic NH₂ position too varying degrees depending on the alkyl halide used. Normally the 2-substituted product is the major isomer and crystallises readily. Chromatography is sometimes necessary. ¹HNMR/c: 1.44 ppm (m, 6H), 4.55 ppm (m, 1H), 5.5 ppm (m, 2H), 7.18 ppm (bs, 1H), 7.35 ppm (bs, 1H).

Example 591 5-Amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile

Add phosphorous oxychloride (99 ml, 1.06 mol) slowly to a stirring solution of 5-amino-2-isopropyl-2H-1,2,3, -triazole-4-carboxamide (94.68 g, 0.56 mol) in anhydrous N,N-dimethylformamide (275 ml). Allow the reaction mixture to stir for three hours, add ice and stir the whole reaction until homogeneous, adjust the to pH 5.5 using ammonia. Extract the organics with diethyl ether and combine ethereal phases, wash with water, dry over magnesium sulphate and finally concentrate in vacuo. Dissolve the residue in 2N hydrochloric acid (825 ml) and heat under reflux for 1 hour. Cool the solution in an ice-water bath and filter to give a yellow/white solid. Extract the aqueous phase with dichloromethane (2×500 ml), combine the organic phase, wash with water, dry over magnesium sulphate, filter and evaporate to give an orange solid. Combine solids and dissolve in dichloromethane and pass through a pad of flash silica (500 g) to give a white solid of 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g, 52% yield): ¹HNMR/c: 1.51 ppm (d, 6H), 4.27 ppm (bs, 2H), 4.62 ppm (m, 1H).

Example 592 2-Isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole-4-carbonitrile

Combine 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g, 0.292 mol) and 2-fluoronitrobenzene (41.25 g, 0.292 mol) in dimethylsulphoxide (590 ml) and stir in the presence of lithium hydroxide monohydrate (24.56 g;0.584 mol) for eighteen hours at 55° C. Pour the reaction mixture onto ice-water, stir for one hour, filter and wash the filter pad well with water to leave a yellow crystalline solid to give 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole4-carbonitrile (73.7 g, 93% yield): ¹HNMR/c: 1.6 ppm (d, 6H), 4.8 ppm (m, 1H), 7.05 ppm (tr, 1H), 7.64 ppm (tr, 1H), 8.2 ppm (dd, 1H), 8.28 ppm (dd, 1H), 10.25 ppm (s, 1H).

Example 593 2-Isopropyl-2,4-dihydro[1,2,3]triazolo[4,5-b][1,5]benzazepin-10-amine hydrochloride

Combine 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole-4-carbonitrile (51.5 g, 0.1 87 mol) in ethanol (700 ml) and warm to 60° C. Add stannous chloride dihydrate (130 g, 0.561 mol) in 5N hydrochloric acid (700 ml) and add as a single portion and heat the resultant mixture under reflux for four hours. Chill the reaction mixture overnight to give the product as yellow crystals and collect by filtration and wash with ethanol. Dry at 50° C. under reduced pressure to give 2-isopropyl-2,4-dihydro[1,2,3]triazolo[4,5-b][1]benzazepin-10-amine hydrochloride (52.1 g, 100% yield).

Example 594 (S)-2-Isopropyl-10-(3-phenethyl-piperazin-1-yl)-2,4-dihydro-1,2,3,4.9-pentaaza-benzo[f]azulene dihydrochloride hemihydrate

Combine 2-isopropyl-2,4-dihydro-1,2,3,4,9-pentaaza-benzo[f]azulen-10-ylamine (0.863 g, 3.56 mmol), (S)-2-phenethyl-piperazine (0.678 g, 3.56 mmol) in NMP (6.0 mL) and heat at 200° C. for 3 hours. Cool to ambient temperature and dilute with water (75 mL). Extract with ethyl acetate to give 1.59 g of the crude product. Silica gel chromatography, eluding with methylene chloride:methanol (100:7.5), to give the title compound as the free base. The dihydrochloride salt precipitates in ethyl acetate as a yellow solid: mp 210° C.; mass spectrum (ion spray): m/z=416 (M+1); Analysis for C₂₄H₃₁Cl₂N₇(0.5 H₂O): calcd: C, 57.95; H, 6.48; N, 19.71; found: C, 58.01; H, 6.22; N, 19.70.

Example 595 (S)-2-Isopropyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-2,4-dihydro-1,2,3,4,9-pentaaza-benzo[f]azulene dihydrochloride hemihydrate

Combine (S)-2-isopropyl-10-(3-phenethyl-piperazin-1-yl)-2,4-dihydro-1,2,3,4,9-pentaaza-benzo[f]azulene (0.59 g, 1.42 mmol)and 37% formaldehyde solution (0.13 mL, 1.56 mmol) in 1,2-dichloroethane (25 mL). Stir for 10 minutes and add sodium triacetoxy borohydride (0.451 g, 2.13 mmol). Stir an additional 30 minutes and then pour solution onto saturated sodium bicarbonate solution. Extract with methylene chloride to give the crude product. Silica gel chromatography, eluding with methylene chloride:methanol (100:2.5), gives the title compound as the free base. The dihydrochloride salt precipitates in ethyl acetate as a yellow solid: m.p. 200° C.; mass spectrum (ion spray): m/z=430 (M+1); Analysis for C₂₅H₃₃Cl₂N₇(0.5 H₂O): calcd: C, 58.71; H, 6.70; N, 19.17; found: C, 58.77; H, 6.60; N, 19.05.

Example 596 (S)-2-(1,4-Dibenzyl-piperazin-2-yl)-1-phenyl-ethanol

Add phenyllithium (11.3 mL, 20.4 mmol, 1.8 M in cyclohexane-ether) dropwise to a −78° C. solution of (S)-(1,4-dibenzyl-piperazin-2-yl)-acetaldehyde (4.2 g, 13.6 mmol) in THF (60 mL). Stir 30 min at −78° C. and 4 h at ambient temperature. Add ice, brine, and extract with ether. Wash the extracts with brine, dry with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 3.98 g (76%) of the title compound: mass spectrum (ion spray): m/z=387 (M+1). HR-MS calculated for C₂₆H₃₁N₂O: 387.2436. Found 387.2442.

Example 597 (S)-1-Phenyl-2-piperazin-2-yl-ethanol

Dissolve (S)-2-(1,4-dibenzyl-piperazin-2-yl)-1-phenyl-ethanol (3.89 g, 10.1 mmol) in ethanol (50 mL). Add ammonium formate (3.8 g, 60.4 mmol), palladium hydroxide (1.6 g, 20 wt. % on carbon) and ethanol (25 mL). Heat to reflux. After 6.5 h, cool and stir at ambient temperature 18 h. Filter the palladium hydroxide and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (10%) then 7N ammonia in methanol-methylene chloride (10%) as the eluent to give 860 mg (41%) of the title compound: mass spectrum (ion spray): m/z=207 (M+1).

Example 598 and Example 599 (S,R)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

(S,S)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

Add methyl trifluoromethanesulfonate (174 μL, 1.53 mmol) to a 0° C. slurry of 2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (315 mg, 1.28 mmol) in dichloromethane (4 mL). Stir 1 h at 0° C. then warm to ambient temperature and stir 18 h. Concentrate the reaction to an orange powder. Add (S)-1-phenyl-2-piperazin-2-yl-ethanol (264 mg, 1.28 mmol) and pyridine (5 mL). Heat to 110° C. for 5.5 h and stir at ambient temperature for 18 h. Concentrate the reaction, dissolve the residue in methanol-dichloromethane, apply to a SCX column. Wash the column with methanol-dichloromethane to remove impurities then elute the product with 2N ammonia in methanol-dichloromethane (10%). Concentrate and purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (2.5%–3%) as the eluent to give 39 mg of (S,R)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol and 130 mg of (S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol.

(S,R)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol: mass spectrum (ion spray): m/z=419 (M+1). HR-MS calculated for C₂₄H₂₇N₄OS: 419.1906. Found 419.1919. ¹H NMR (DMSO-d6): δ 7.55 (s, 1H), 7.37–7.26 (m, 4H), 7.25–7.17 (m, 1H), 6.87–6.73 (m, 3H), 6.67 (br d, 1H), 6.30 (s, 1H), 5.52 (br s, 1H), 4.75–4.66 (m, 1H), 3.84 (br d, 1H), 3.72 (br d, 1H), 2.88 (d, 1H), 2.82–2.60 (m, 3H), 2.56–2.45 (m, 1H), 2.41 (br s, 1H), 2.26 (s, 3H), 1.50–1.73 (m, 2H).

(S,S)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol: mass spectrum (ion spray): m/z=419 (M+1). HR-MS calculated for C₂₄H₂₇N₄OS: 419.1906. Found 419.1909. ¹H NMR (DMSO-d₆): δ 7.56 (s, 1H), 7.37–7.15 (m, 5H), 6.87–6.74 (m, 3H), 6.67 (br d, 1H), 6.31 (s, 1H), 5.29 (br s, 1H), 4.74–4.67 (m, 1H), 3.88 (br d, 1H), 3.80 (br d, 1H), 2.86 (d, 1H), 2.80–2.59 (m, 3H), 2.53–2.42 (m, 2H), 2.28 (s, 3H), 1.62–1.53 (m, 2H).

Example 600 (S,S)-2-[1-Methyl-4-(2-methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

Add formaldehyde (33 μL, 0.42 mmol, 37% in water) to a solution of (S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol (160 mg, 0.38 mmol) in methylene chloride (6 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (121 mg, 0.57 mmol) and stir 2 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–5%) as the eluent to give 70 mg (42%) of the title compound: mass spectrum (ion spray): m/z=433 (M+1), 431 (M−1). HR-MS calculated for C₂₅H₂₉N₄OS: 433.2062. Found 433.2061. ¹H NMR (DMSO-d₆): δ 7.60 (s, 1H), 7.36–7.17 (m, 5H), 6.88–6.75 (m, 3H), 6.68 (br d, 1H), 6.35 (s, 1H), 5.34 (br d, 1H), 4.60–4.50 (m, 1H), 3.85 (br d, 1H), 3.70 (br d, 1H), 3.04–2.92 (m, 1H), 2.85–2.66 (m, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.20–2.10 (m, 1H) 2.08–1.98 (m, 1H), 1.97–1.85 (m, 1H), 1.66–1.52 (m, 1H).

Example 601 and Example 602 (S,R)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

(S,S)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

Add methyl trifluoromethanesulfonate (806 μL, 7.13 mmol) to a 0° C. slurry of 2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (1.31 g, 4.75 mmol) in dichloromethane (15 mL). Stir 18 h, gradually allowing reaction to warm to ambient temperature. Concentrate the reaction to an orange powder. Add (S)-1-phenyl-2-piperazin-2-yl-ethanol (980 mg, 4.75 mmol) and pyridine (11 mL). Heat to 115° C. for 5 h. Concentrate and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (0%–10%) then 7N ammonia in methanol-methylene chloride (20%) as the eluent to give 520 mg. Purify again, in two portions, by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (2.5%–4.5%) as the eluent to give 28 mg of (S,R)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol and 155 mg of (S,S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol after combining both radial purifications.

(S,R)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol: mass spectrum (ion spray): m/z=448 (M+1), 446 (M−1). HR-MS calculated for C₂₅H₃₀N₅OS: 448.2171. Found 448.2181.¹H NMR (DMSO-d₆): δ 7.78 (s, 1H), 7.37–7.16 (m, 5H), 6.89–6.73 (m, 3H), 6.67 (br d, 1H), 5.44 (br s, 1H), 4.74–4.67 (m, 1H), 4.04–3.87 (m, 2H), 3.05 (quintet, 1H), 2.93–2.79 (m, 2H), 2.76–2.54 (m, 3H), 1.73–1.60 (m, 1H), 1.59–1.47 (m, 1H), 1.21 (d, 6H).

(S,S)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol: mass spectrum (ion spray): m/z=448 (M+1), 446 (M−1). HR-MS calculated for C₂₅H₃₀N₅OS: 448.2171. Found 448.2156. ¹H NMR (DMSO-d₆): δ 7.80 (s, 1H), 7.35–7.16 (m, 5H), 6.90–6.74 (m, 3H), 6.68 (br d, 1H), 5.44 (br s, 1H), 4.75–4.63 (m, 1H), 4.19–3.89 (m, 2H), 3.08 (quintet, 1H), 2.90–2.50 (m, 5H), 1.64–1.51 (m, 2H), 1.23 (d, 6H).

Example 603 (S,S)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-1-methyl-piperazin-2-yl]-1-phenyl-ethanol

Add formaldehyde (23 μL, 0.29 mmol, 37% in water) to a solution of (S,S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol (117 mg, 0.26 mmol) in dichloroethane (5 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (83 mg, 0.39 mmol) and stir 2 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 68 mg (56%) of the title compound: mass spectrum (ion spray): m/z=462 (M+1), 460 (M−1). HR-MS calculated for C₂₆H₃₂N₅OS: 462.2328. Found 462.2322. ¹H NMR (DMSO-d6): δ 7.82 (s, 1H), 7.35–7.18 (m, 5H), 6.91–6.76 (m, 3H), 6.69 (br d, 1H), 5.29 (s, 1H), 4.58–4.46 (m, 1H), 4.14–3.77 (m, 2H), 3.02–3.17 (m, 2), 2.90 (dd, 1H), 2.74–2.65 (m, 1H), 2.28–2.11 (m, 1H), 2.14 (s, 3H), 2.03–1.84 (m, 2H) 1.70–1.54 (m, 1H), 1.26 (d, 6H).

Example 604 2-(2-Nitro-phenylamino)-5-trifluoromethyl-benzonitrile

Add cesium carbonate (1.3 g, 4 mmol) to a solution of 2-nitro-aniline (276 mg, 2 mmol) and 2-fluoro-5-trifluoromethyl-benzonitrile (378 mg, 2 mmol) in DMF (10 mL) at room temperature then stir the resulting dark red solution at room temperature for 16 hours and 2 hours at 50° C. Cool down and pour into a mixture of ice and concentrated hydrochloric acid (50 mL, v/v). Extract the aqueous phase with dichloromethane (3×300 mL), wash with water and brine and dry over MgSO₄ to yield the titled compound as a yellow solid (480 mg, 80%): mp 160–161° C.; ¹H NMR (CDCl₃) δ 7.14 (ddd, 1H), 7.48 (dd, 1H), 7.58 (dd, 1H), 7.60 (d, 1H), 7.76 (dd, 1H), 7.92 (d, 1H), 8.27 (dd, 1H), 9.63 (bs, 1H). MS (ES/neg) m/z (rel intensity) 306.1 (100).

Example 605 2-Trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride salt

Add a solution of tin(II) chloride (567 mg, 3 mmol) in 12 N hydrochloric acid (1.8 mL) to a solution of 2-(2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (307 mg, 1 mmol) in ethanol (10 mL). Reflux for 24 hours, then concentrate under vacuum, add water and filter. Wash the resulting solid with water and dichloromethane then dry under vaccum to yield the titled compound as a yellow solid (282 mg, 90%): mp 334–336° C.; ¹H NMR (DMSO-d₆) δ 7.05–7.19 (m, 4H), 7.34 (d, 1H), 7.86 (dd, 1H), 7.87 (s, 1H), 8.79 (s, 1H), 9.26 (s, 1H), 9.75 (s, 1H), 12.40 (s, 1H). MS (ESI/neg) m/z (rel intensity) 276.1 (100).

Example 606 11-(4-Methyl-piperazin-1-yl)-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine

By a method similar to Example 59, 2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride salt (600 mg, 1.9 mmol) and N-methyl piperazine (960 mg, 9.6 mmol) afforded the title compound as a yellow solid (555 mg, 81%): mp 68–72° C.; ¹H NMR (CDCl₃) δ 2.36 (s, 3H), 2.53 (bs, 4H), 3.42 (m, 4H), 5.12 (s, 1H), 6.70 (d, 1H), 6.90 (d, 1H), 6.92 (dt, 1H), 7.01 (dd, 1H), 7.10 (d, 1H), 7.52 (d, 1H), 7.55 (s, 1H); ¹⁹F NMR (CDCl₃) δ −328.38; MS (ESI/neg) m/z (rel intensity) 359.2 (100).

Example 607 2-(4-Fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile

Combine 4-fluoro-2-nitro-phenylamine (5.9 g, 32.03 mmol), 2-fluoro-5-trifluoromethyl-benzonitrile (6.07 g, 32.03 mmol) and lithium hydroxide monohydrate (4.03 g, 96.08 mmol) in methyl sulfoxide (DMSO, 60 ml). Heat the resulting mixture to 70° C. for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 400 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate. Obtained 9.995 g of the title compound (30.73 mmol, 96% yield) as an orange amorphous solid. Product used as is with no further purification: Mass Spectrum (m/e): 326(M+1).

Example 608 8-Fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride

Heat a solution of 2-(4-fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (9.995 g, 30.73 mmol) in ethanol (170 ml) to 60° C. Add to a solution of tin (II) chloride (29.1 g, 153.67 mmol) in 5.0 N hydrochloric acid (170 ml) and heat to reflux. After 18 hours, cool the reaction to room temperature and place in a freezer for 24 hours. The product precipitates from the solution and is collected by filtration. Obtained 2.253 g of the title compound (6.79 mmol, 22% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 296(M+1).

Example 609 8-Fluoro-11-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine succinate

Heat a solution of 8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.2 g, 0.60 mmol) and diisopropylethylamine (0.086 g, 0.66 mmol) in 1-methyl-2-pyrrolidinone (4mL) to 60° C. for 30 minutes. Add 2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.398 g, 1.81 mmol) and heat the reaction mixture to 195° C. for 14 hours. Cool reaction mixture to ambient temperature. Dilute with 50 ml of ethyl acetate and wash twice with saturated aqueous sodium chloride then twice with water. Collect the organic layer and dry over sodium sulfate. Remove solvent under reduced pressure. Purification via flash chromatography, eluting with a linear gradient starting with 100% dichloromethane and going to 85% dichloromethane with 15% 2M ammonia in methanol, gives the free base of the title compound (0.107 g, 0.21 mmol, 36% yield) as a yellow amorphous solid. Convert the product to the succinate salt by dissolving the product in methanol and adding one equivalent of succinic acid, swirl or sonicate the mixture until no solid succinic acid remains, then removing the solvent under reduced pressure gives the title compound: Mass Spectrum (m/e): 499(M+1); Exact Mass Spec: Calc. 499.2121; Found 499.2136.

Example 610 8-Fluoro-11-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine

Dissolve the free base obtained from Example 609 (0.078 g, 0.16 mmol) in dichloromethane (8 ml). Add sodium triacetoxyborohydride (0.066 g, 0.31 mmol) and formaldehyde (0.005 g, 0.16 mmol, 0.013 g of a 37% aqueous solution) and stir the mixture for two hours at ambient temperature. Dilute the mixture with saturated aqueous sodium chloride (50 mL) and extract three times with dichloromethane. Combine the organic layers, dryover sodium sulfate and remove the solvent under reduced pressure. Purification via flash chromatography, eluting with a linear gradient starting with 100% of a stock mixture of 80% dichloromethane with 20% hexanes and going to 85% of the stock mixture with 15% 2M ammonia in methanol, gives the free base of the title compound (0.062 g, 0.12 mmol, 77% yield) as a yellow amorphous solid. It is then converted to the succinate salt as described previously: Mass Spectrum (m/e): 513(M+1); Exact Mass Spec: Calc. 513.2278; Found 513.2284.

Example 611 8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine

Heat a solution of 8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.2 g, 0.60 mmol) and diisopropylethylamine (0.086 g, 0.66 mmol) in 1-methyl-2-pyrrolidinone (4 mL) to 60° C. After 30 minutes, add 2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.38 g, 1.81 mmol) and heat the reaction mixture to 195° C. for 16 hours. Cool reaction mixture to ambient temperature. Dilute with of ethyl acetate (50 ml) and wash twice with saturated aqueous sodium chloride then twice with water. Collect the organic layer and dry over sodium sulfate. Remove solvent under reduced pressure. Purification via flash chromatography, eluting with a linear gradient starting with 100% dichloromethane and going to 85% of dichloromethane with 15% 2M ammonia in methanol, gives the free base of the title compound (0.083 g, 0.17 mmol, 28% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 487(M+1).

Example 612 8-Fluoro-1-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine

Dissolve the product obtained from Example 611 (0.083 g, 0.17 mmol) in dichloromethane (8 ml). Add sodium triacetoxyborohydride (0.072 g, 0.34 mmol) and formaldehyde (0.005 g, 0.17 mmol, 0.014 g of a 37% aqueous solution) and stir the mixture for two hours at ambient temperature. Dilute the mixture with of saturated aqueous sodium chloride (50 mL) and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and remove the solvent under reduced pressure. Purification via flash chromatography, eluting with a linear gradient starting with 100% of dichloromethane and going to 85% dichloromethane with 15% 2M ammonia in methanol, gives the free base of the title compound (0.032 g, 0.06 mmol, 37% yield) as a yellow amorphous solid. It is then converted to the succinate salt as described previously: Mass Spectrum (m/e): 501(M+1); Exact Mass Spec. Calc 501.2078; Found 501.2093.

Receptor Binding Assays

Serotonin 5-HT₆ and Dopamine D₂ Binding Assay Protocol

The assay buffers used are 50 mM Tris-HCl pH 7.4, 120 mM NaCl, 5 mM KCl, 5 mM MgCl₂, 1 mM EDTA for the Dopamine D₂s receptor binding assay. The radioligand used is [¹²⁵I]iodospiperone from New England Nuclear Cat #NEX284-2200 Ci/mmole. The membranes used are from Receptor Biology (now owned by NEN), Cat #RBHD2CM for the D₂ receptor.

Compounds are obtained as 10 mM stocks in 100% DMSO. They are diluted to 1 mM in 100% DMSO by adding 180 μL DMSO to 20 μL of stock in 96 well plates using a multidrop. The 1 mM stocks are then diluted to make an 11 point concentration range from 125 μM down to 1.25 μM in half log increments using 10% DMSO as diluent. This is done using a TECAN robot. The final DMSO at this stage is 10–21.25% DMSO

The radioligand is diluted in assay buffer to provide 0.1 nM for the D₂ assay. Each vial of membranes is diluted up to 92 mL in assay buffer. The final assay volume is 250 μL consisting of 210 μl of diluted membranes, 20 μL of compound or 10% DMSO for total binding, and 20 μL of diluted radioligand. The compounds are transferred from drug dilution plates into coming 96 well assay plates using a 96 well Multimek pipettor. Radioligand and membranes are added to assay plates using multidrop pipettors. Non-specific binding is determined in wells containing a final concentration of 5 μM haloperidol. The final drug concentration range in half logs is from 10 μM down to 0.1 nM. The final DMSO in the assay is 1–1.7%.

After addition of drug, membrane, and ligand, the plates are incubated for 2 hours at room temperature. During this time 96 well Millipore filter plates (MAFBNOB50) are soaked for a least 30 minutes with 200 μL per well of 0.5% polyethyleneimine.

The 0.5% PEI is removed from filterplate wells using a TiterTek MAP aspirator and 200 μL of the incubation mixture is transferred from the incubation plate to the filterplate after mixing. This transfer is done using the 96 tip Mutimek pipettor. After transfer to the filterplate filterplates are extracted and ished twice with 220 μL per well of cold buffer on the MAP aspirator. The peel away bottoms are removed from the filterplates and 60 μL per well of microscint 20 scintillation fluid is added per well using a multidrop. Plates are placed into suitable holders and are left at room temperature for 3 hours and are counted for ³H in either a Wallac Microbeta counter or on a Packard Topcount.

[¹²⁵I]DOI SPA Binding to Rhesus 5-HT_(2A) Receptors Protocol

Incubations are performed in a total volume of 200 μl in 96 well assay plates. 50 μL [¹²⁵I]DOI (NEN, 2200 Ci/mmol, final concentration=0.075nM) is added to 50 μL of test compounds dissolved in water (±DMSO and/or glacial acetic acid). 50 μL Wheat Germ Agglutinin (WGA) SPA beads, at 1 mg/well, (Amersham Life Sciences) in assay buffer (67mM Tris-HCl pH 7.4, 13mM MgCl₂, 0.67 mM EDTA) are then added. Membrane homogenate from cells expressing rhesus 5-HT_(2A) receptors, approximately 0.9 million cells/well, is added last. The plates are covered with sealing tape (FasCal) and allowed to incubate at room temperature for 2 hours. The plates are then centrifuged at approximately 200× g for 10 minutes at room temperature. The amount of ¹²⁵I-DOI bound to the membranes, i.e. proximate to the WGA SPA beads, is then determined using a Wallac MicroBeta Trilux Scintillation Counter (Wallac, Inc.).

Pharmaceutical Formulations

Capsule

A pulvule formulation is prepared by blending the active with silicone starch, and filling it into hard gelatin capsules.

Per 300 mg capsule Compound of formula (I)  5.0 mg Silicone  2.9 mg Starch flowable 292.1 mg Tablet

A tablet formulation is made by granulating the active with appropriate diluent, lubricant, disintegrant and binder and compressing.

Per 300 mg tablet Compound of formula (I)  10.0 mg Magnesium stearate  0.9 mg Microcrystalline cellulose  75.0 mg Povidone  15.0 mg Starch, directly compressible 199.1 mg Injection

An aqueous injection of active is prepared as a freeze-dried plug, for reconstitution in a suitable, sterile diluent before use (to a total volume of 10 ml).

Compound of formula (I) 20.0 mg Mannitol 20.0 mg N Hydrochloric acid and/or N sodium hydroxide to adjust pH to 5–5.5. Controlled Release Injection

A controlled release injection for intramuscular injection is formed from a sterile suspension of micronised active in an oleaginous vehicle.

Compound of formula (I) 65.0 mg Aluminium stearate 0.04 mg Sesame oil   2 ml 

1. A compound of formula (I):

wherein, A is

ALK is (C₁₋₄) alkylene optionally substituted with OH, methoxy, ethoxy, or F; Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic; R¹ is hydrogen or (C₁₋₄) alkyl optionally substituted with OH, OR³, or OCH₂CH₂OH; R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, OR⁴, SR⁴, NO₂, CN, COR⁴, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, NR⁵COR⁴, NR⁵SO₂R⁴, or optionally substituted phenyl; R³ is (C₁₋₂) alkyl; R⁴ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁵ and R⁶ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; Z is absent or is one or two substituents independently selected from halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OR⁷, SR⁷, NO₂, CN, COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁷, NR⁸R⁹, or optionally substituted phenyl; R⁷ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁸ and R⁹ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1 in which ALK is —CH₂— or —CH₂CH₂—.
 3. A compound of claim 2 in which Ar is optionally substituted phenyl, furan, or thiophene.
 4. A compound of claim 3 in which R¹ is hydrogen, methyl, or —CH₂CH₂—O—CH₂CH₂—OH.
 5. A compound of claim 4 in which R² is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, or halogen.
 6. A compound of claim 5 in which Z is absent or is halogen.
 7. A compound of claim 6 in which the stereo configuration is “S” about the carbon of the piperazine group bound to ALK.
 8. A compound of claim 6 in which the stereo configuration is “R” about the carbon of the piperazine group bound to ALK.
 9. A pharmaceutical composition comprising an effective amount of a compound of claim 1 in association with a pharmaceutically acceptable carrier, diluent or excipient. 